The EINSTEIN PE Study 'Xarelto' for the Acute and Continued Treatment of Symptomatic Pulmonary Embolism

Effective PE Treatment Matters PE is a potentially fatal consequence of DVT PE is frequently asymptomatic, and along with DVT, is associated with delayed diagnosis, making prompt treatment difficult1 More than 90% of deaths occur in untreated patients, because of unrecognized symptoms of PE2 Diagnosis of VTE >10 days from onset of symptoms (%)2 A Crucial Need for Effective PE Treatment Early diagnosis is important to prevent progression of PE, because approximately 10% of symptomatic PE cases are fatal within 1 hour of first symptoms3,4 More than 90% of deaths seem to occur in untreated patients, because of unrecognized symptoms2 Associated symptoms of PE include dyspnoea, chest pain and syncope. However, symptoms can be non-specific, or even absent, making diagnosis difficult.2,5 Diagnostic tools and clinical probability scores, such as the Wells score, can be used to confirm or exclude DVT or PE2,6,7 The risk of recurrence is similar following DVT or PE;8 however, the risk of PE-associated mortality is considerably higher in those who experience an initial PE episode, owing to the increased likelihood of the subsequent recurrent events being PE rather than DVT9 Abbreviations DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism References Ageno W et al. Thromb Res 2008;121:751–756 Torbicki A et al. Eur Heart J 2008;29:2276–2315 Stein PD et al. Chest 1995;108:978–981 Bell WR et al. Am Heart J 1982;103:239–261 Blann AD et al. BMJ 2006;332;215-219 Wells PS et al. Lancet 1997;350:1795–1798 Wells PS et al. Thromb Haemost 2000;83:416–420 Kearon C. Circulation 2003;107(23 Suppl 1):I22–I30 Kearon C. Clin Chest Med 2003;24:63–72 1. Ageno et al, 2008; 2. Torbicki et al, 2008

'Xarelto': Simple and Effective Single-Drug Approach for VTE Treatment 'Xarelto' is fast-acting and has minimal drug–drug interactions1 'Xarelto' has no need for routine monitoring or frequent dose adjustment1 'Xarelto' exerts similar pharmacodynamic effects to enoxaparin2 40 30 20 10 4 8 12 16 24 Anti-Factor Xa activity (ng/ml enoxaparin) Time (hours) Enoxaparin (n=10) 'Xarelto' (n=11) 'Xarelto' as an Alternative Treatment Option for VTE Traditional approaches for VTE treatment involve initial heparin therapy for 5–10 days, overlapping with and followed by a VKA3,4 Drawbacks are associated with dual-drug therapy and include the need for parenteral administration of LMWH, and the need for coagulation monitoring and dose adjustment with VKAs. VKAs also have a narrow therapeutic window and exhibit multiple drug and food interactions5 'Xarelto' is an oral, direct Factor Xa inhibitor that has been investigated in phase III clinical trials, and has many of the characteristics required in an ideal anticoagulant: A rapid onset of action similar to enoxaparin,2 with maximum plasma concentrations occurring 2–4 hours after tablet intake6 No requirement for routine coagulation monitoring or frequent dose adjustments based on age, gender, body weight or renal function6 Minimal food and drug interactions6 'Xarelto' has been investigated for the treatment and secondary prevention of DVT and PE in the EINSTEIN programme,7,8 and is the only novel oral anticoagulant investigated in a dedicated PE study Approval in the EU, US and Canada for the treatment of PE and secondary prevention of DVT and PE – specifically, haemodynamically stable PE patients who do not require thrombolysis or pulmonary embolectomy – is based on the pivotal EINSTEIN PE study, the largest ever conducted in the acute treatment of PE in >4,800 patients Abbreviations DVT, deep vein thrombosis; LMWH, low molecular weight heparin; PE, pulmonary embolism; VKA, vitamin K antagonist; VTE, venous thromboembolism References Perzborn E et al. Nat Rev Drug Discov 2011;10:61–75 Kubitza D et al. Clin Pharmacol Drug Dev 2013; 2:270–277 Kearon C et al. Chest 2012;141:e419S–e494S Torbicki A et al. Eur Heart J 2008;29:2276–2315 Eriksson BI et al. Ann Rev Med 2011;62:41–57 Bayer Pharma AG. Xarelto (rivaroxaban) Summary of Product Characteristics 2013 The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510 The EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–1297 'Xarelto' acts as fast as enoxaparin and can be given at the initiation of DVT and PE treatment 1. Perzborn et al, 2011; 2. Kubitza et al, 2013

The EINSTEIN PE Study Design Included an Initial Intensified Regimen of 'Xarelto' A single-drug approach with 'Xarelto' was used in the pivotal EINSTEIN PE study - the largest ever conducted in the acute treatment of PE, involving haemodynamically stable patients An intensified dose of 'Xarelto' (15 mg bid) was given for the first 21 days to provide protection when patients are at highest risk of recurrence After 21 days, 'Xarelto' 20 mg od was given to provide continued protection against VTE recurrence Primary efficacy outcome: symptomatic recurrent VTE (composite of recurrent DVT, non-fatal PE or fatal PE) Principal safety outcome: composite of major or clinically relevant non-major bleeding 15 mg bid Objectively confirmed PE with or without symptomatic DVT N=4832 'Xarelto' Day 1 Day 21 Enoxaparin (1.0 mg/kg) bid for at least 5 days, plus VKA target INR 2.5 (INR range 2.0–3.0) Predefined treatment period of 3, 6 or 12 months 20 mg od R 30-day observation period The EINSTEIN PE Study EINSTEIN PE was an event-driven, non-inferiority study that investigated the efficacy and safety of 'Xarelto' compared with standard of care in 4833 randomized patients (n=4832 owing to one invalid informed consent) with acute, objectively confirmed symptomatic PE, with or without symptomatic DVT1 Patients received 'Xarelto' (15 mg bid for 21 days; followed by 20 mg od), or subcutaneous enoxaparin followed by a VKA (either warfarin or acenocoumarol) for 3, 6 or 12 months. The VKA dose was adjusted to maintain an INR of 2.0–3.01 Rationale for the dosing regimen stemmed from dose-finding studies, which showed that an intensified 'Xarelto' dose was well-tolerated and effective in the treatment of acute symptomatic DVT, as suggested by a reduction in thrombus burden2,3 Because the dose selected for the phase III studies was based on data from patients with DVT, EINSTEIN PE included a dose confirmation stage in the first 400 patients, to ensure that the selected dose was also effective for the treatment of patients with PE1 Ineligible patients included those in whom pulmonary embolectomy had been performed, or who received thrombolytic therapy Bleeding was defined as major if it was clinically overt and associated with a fall in the haemoglobin level of ≥20 g/l, or if it led to transfusion of ≥2 units of red cells, or if it was intracranial or retroperitoneal, occurred in another critical site or contributed to death1 Bleeding was defined as non-major (but clinically relevant) if it was overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, unscheduled contact with a physician, interruption or discontinuation of study treatment, or associated with any other discomfort such as pain or impairment of activities of daily life1 Abbreviations bid, twice daily; DVT, deep vein thrombosis; INR, international normalized ratio; od, once daily; PE, pulmonary embolism; R, randomization; VKA, vitamin K antagonist; VTE, venous thromboembolism References The EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–1297. Agnelli G et al. Circulation 2007;116:180–187 Büller H et al. Blood 2008;112:2242–2247 The EINSTEIN–PE Investigators, 2012

Effective PE Treatment Matters 'Xarelto' Enoxaparin/VKA n (%) First symptomatic recurrent VTE 50 (2.1) 44 (1.8) Recurrent DVT 18 (0.7) 17 Recurrent DVT + PE 2 (<0.1) Non-fatal PE 22 (0.9) 19 (0.8) Fatal PE/unexplained death where PE cannot be ruled out 10 (0.4) 6 (0.3) 3.0 2.5 2.0 1.5 1.0 0.0 0.5 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) 'Xarelto' (N=2419) Enoxaparin/VKA (N=2413) HR=1.12 (95% CI 0.75–1.68) p=0.003 (non-inferiority) p=0.57 (superiority) Cumulative event rate (%) 'Xarelto' also showed consistent efficacy across subgroups 'Xarelto' as Effective as Standard of Care Recurrent VTE occurred in 2.1% and 1.8% of patients receiving 'Xarelto' and enoxaparin/VKA, respectively, which was shown to be statistically non-inferior for 'Xarelto' (p=0.003)1 By day 21 (the end of 'Xarelto' bid dosing), the primary efficacy outcome had occurred in 0.7% of patients who received 'Xarelto' and in 0.9% of patients who received enoxaparin/VKA1 Recurrent DVT events were confirmed in 0.7% of both treatment groups1 A total of 0.9% and 0.8% non-fatal PE events occurred in the 'Xarelto' and enoxaparin/VKA treatment groups, respectively; the numbers of fatal PE cases or unexplained deaths were similar between patients who received 'Xarelto' compared with enoxaparin/VKA (0.4% vs 0.3%, respectively)1 Abbreviations bid, twice daily; CI, confidence interval; HR, hazard ratio; PE, pulmonary embolism; VKA, vitamin K antagonist; VTE, venous thromboembolism Reference The EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–1297 'Xarelto' and standard of care had similar efficacy in the reduction of symptomatic recurrent VTE Intention-to-treat population The EINSTEIN–PE Investigators, 2012

Safety Matters: Similar Rates of Clinically Relevant Bleeding 30 60 90 120 150 180 210 240 270 300 330 360 15 14 10 13 12 11 9 8 7 6 5 4 3 2 1 Time to event (days) 'Xarelto' (N=2412) Enoxaparin/VKA (N=2405) Cumulative event rate (%) 'Xarelto' also showed consistent safety across subgroups Major or clinically relevant non-major bleeding 'Xarelto' n/N (%) Enoxaparin/VKA n/N (%) HR (95% CI) p-value 249/2412 (10.3) 274/2405 (11.4) 0.90 (0.76–1.07) p=0.23 'Xarelto' Showed Similar Rates of Clinically Relevant Bleeding to Standard of Care Composite rates of major or clinically relevant non-major bleeding occurring during treatment were similar between patients receiving 'Xarelto' and enoxaparin/VKA (10.3% vs 11.4%, respectively; p=0.23)1 Abbreviations CI, confidence interval; HR, hazard ratio; VKA, vitamin K antagonist Reference The EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–1297 Safety population The EINSTEIN–PE Investigators, 2012

Significant Reduction: Halving the Risk of Major Bleeding 'Xarelto' Enoxaparin/VKA HR (95% CI) p-value n (%) Major bleeding 26 (1.1) 52 (2.2) 0.49 (0.31–0.79) p=0.003 Fatal 2 (<0.1) 3 (0.1) Non-fatal critical site 7 (0.3) Intracranial 1 10 (0.4) Retroperitoneal 3.0 2.5 2.0 1.5 1.0 0.5 30 60 90 120 150 180 210 240 270 300 330 360 Cumulative event rate (%) Time to event (days) 'Xarelto' (N=2412) Enoxaparin/VKA (N=2405) 'Xarelto' Showed a Significant Reduction in Major Bleeding Compared with Standard of Care Rates of major bleeding were significantly reduced in patients who received 'Xarelto' compared with enoxaparin/VKA (1.1% vs 2.2%, respectively; p=0.003)1 This included reductions in intracranial bleeding,1 which is one of the complications most feared by physicians Abbreviations CI, confidence interval; HR, hazard ratio; VKA, vitamin K antagonist Reference The EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–1297 'Xarelto' reduced major bleeding by 51% compared with standard of care, with large reductions in critical site bleeding Safety population The EINSTEIN–PE Investigators, 2012

'Xarelto' can be Used in a Wide Range of Haemodynamically Stable PE Patients Efficacy and safety outcomes were consistent across key patient subgroups, including elderly patients and those with renal impairment 'Xarelto' was effective regardless of the severity of PE, whether it was anatomically limited (≤25% of vasculature of a single lobe) or extensive (multiple lobes and >25% of entire pulmonary vasculature) 'Xarelto' was associated with a similar rate of adverse events compared with standard of care This included serious adverse events and treatment-emergent adverse events There was no evidence of liver toxicity in patients who received 'Xarelto' 'Xarelto' can be Used in a Wide Range of Haemodynamically Stable PE Patients Impaired renal function, low or high body weight and older age are all patient characteristics that may contribute to clinically challenging VTE treatment. 'Xarelto' was effective and well-tolerated across these and other patient subgroups, which included extensive PE1 Adverse event rates were similar between 'Xarelto' and enoxaparin/VKA treatment groups (80.5% vs 79.1%, respectively)1 Serious adverse events, or those leading to prolonged hospitalization or treatment discontinuation, were also similar between treatment groups1 Vascular event rates were similar between patients who received 'Xarelto' and enoxaparin/VKA during treatment; these included acute coronary events (0.6% vs 0.9%), cerebrovascular events (0.5% in both groups) and systemic embolism (0.2% vs 0.1%)1 Increases in liver enzymes (defined as the combination of an alanine aminotransferase level exceeding three times the upper limit of the normal range and a bilirubin level exceeding twice the upper limit of the normal range) were observed in 0.2% of patients in both the 'Xarelto' and enoxaparin/VKA treatment groups1 Abbreviations PE, pulmonary embolism; VKA, vitamin K antagonist; VTE, venous thromboembolism Reference The EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–1297 The EINSTEIN–PE Investigators, 2012

Patients Matter: Improved Treatment Satisfaction with 'Xarelto' A subanalysis of patients in EINSTEIN PE showed that 'Xarelto' was associated with improved treatment satisfaction in patients with PE, compared with standard of care1 This included a reduction in patient-reported anticoagulation burden and an increase in convenience1 'Xarelto' offers increased patient satisfaction, potentially improving compliance compared with standard of care Treatment Satisfaction with 'Xarelto' in Patients with PE Appropriate measurement of treatment satisfaction with novel oral anticoagulants can be achieved through validated patient-reported outcomes A subanalysis of EINSTEIN PE involving approximately 2400 patients was performed, which compared 'Xarelto' with standard of care from the patient perspective1 Patient satisfaction was measured using the Anti-Clot Treatment Scale (ACTS). 'Xarelto' was associated with a lower treatment burden, higher perceived benefits and improved treatment satisfaction compared with enoxaparin/VKA1 Use of a single-drug approach with 'Xarelto' in patients with PE may, therefore, contribute to increased patient compliance and treatment adherence, in addition to simplifying treatment and improving health outcomes Abbreviations PE, pulmonary embolism; VKA, vitamin K antagonist Reference Prins M et al. Blood (ASH Annual Meeting Abstracts) 2012;120:1163 1. Prins et al, 2012

'Xarelto': Simple PE Management from Hospital to Home 'Xarelto' is the only novel oral anticoagulant investigated in a dedicated PE study EINSTEIN PE confirmed the benefits of the simple, single-drug approach with 'Xarelto' in haemodynamically stable PE patients Similar efficacy and safety outcomes compared with standard of care Significant reduction in major bleeding events by 51% compared with standard of care, including intracranial haemorrhage and retroperitoneal bleeding 'Xarelto' Provides Simple Management from Hospital to Home In EINSTEIN PE, a single-drug approach with 'Xarelto' was shown to be non-inferior to enoxaparin/VKA in the reduction of recurrent VTE 'Xarelto' was associated with a 51% reduction in major bleeding, and rates of clinically relevant bleeding were similar 'Xarelto' has the potential to be used effectively in a wide range of patients with PE, including those with unprovoked PE or extensive disease In the treatment of PE, a simple, single-drug approach with 'Xarelto' is likely to provide: Effective and well-tolerated treatment Increased patient compliance, treatment adherence and patient satisfaction Effective Immediate and continued anticoagulation, protecting the patient from risk of recurrent events A favourable benefit–risk profile in a wide range of patients with PE compared with standard of care Abbreviations PE, pulmonary embolism; VKA, vitamin K antagonist; VTE, venous thromboembolism Consistent efficacy and safety results across key patient subgroups

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Patient Characteristics: Similar in Both Study Arms in EINSTEIN PE 'Xarelto' (N=2419) Enoxaparin/VKA (N=2413) Male patients (%) 54.1 51.7 Age, mean, years 57.9 57.5 Weight, kg ≤50 kg 1.6 1.8 >50–100 kg 84.1 83.3 >100 kg 14.3 14.9 Creatinine clearance (%) <30 ml/min 0.2 <0.1 30–49 ml/min 8.6 7.9 50–79 ml/min 26.3 24.6 ≥80 ml/min 64.3 67.0 Patient Characteristics in EINSTEIN PE Overall, similar characteristics were observed between patients who received 'Xarelto' or enoxaparin/VKA1 A range of patients with PE were represented in EINSTEIN PE – a proportion of those enrolled had renal impairment, unprovoked VTE, active cancer or extensive anatomical PE1 Anatomically limited PE was defined as that occupying ≤25% of the vasculature of a single lobe, while extensive PE was defined as that occurring in multiple lobes and >25% of the entire pulmonary vasculature1 Approximately 95% of patients studied received treatment for 6 months or longer1 It is also worth noting that initial heparin treatment was administered for 2 days or less in ~92% of patients1 Abbreviations PE, pulmonary embolism; VKA, vitamin K antagonist; VTE, venous thromboembolism Reference The EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–1297 Intention-to-treat population The EINSTEIN–PE Investigators, 2012

Patient and Treatment Characteristics: Similar in Both Study Arms in EINSTEIN PE 'Xarelto' (N=2419) Enoxaparin/VKA (N=2413) Intended treatment duration (%) 3 months 5.3 5.1 6 months 57.3 57.5 12 months 37.4 37.5 Anatomical extent baseline PE (%) Limited (single lobe, ≤25% of vasculature) 12.8 12.4 Intermediate 59.0 Extensive (multiple lobes, >25% of entire vasculature) 24.7 23.9 Pretreatment with LMWH/heparin/fondaparinux ≤48 h (%) 92.5 92.1 Active cancer (%) 4.7 4.5 Unprovoked PE (%) 64.7 64.3 Patient Characteristics in EINSTEIN PE Overall, similar characteristics were observed between patients who received 'Xarelto' or enoxaparin/VKA1 A range of patients with PE were represented in EINSTEIN PE – a proportion of those enrolled had renal impairment, unprovoked VTE, active cancer or extensive anatomical PE1 Anatomically limited PE was defined as that occupying ≤25% of the vasculature of a single lobe, while extensive PE was defined as that occurring in multiple lobes and >25% of the entire pulmonary vasculature1 Approximately 95% of patients studied received treatment for 6 months or longer1 It is also worth noting that initial heparin treatment was administered for 2 days or less in ~92% of patients1 Abbreviations PE, pulmonary embolism; VKA, vitamin K antagonist; VTE, venous thromboembolism Reference The EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–1297 Intention-to-treat population The EINSTEIN–PE Investigators, 2012

Bleeding Management in Clinical Practice If bleeding events occur while patients are receiving 'Xarelto', they can be managed easily by measures used in clinical practice1,2 There is no specific reversal agent currently available for 'Xarelto'; however, studies are ongoing3–5 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 Bleeding Management in Clinical Practice Bleeding complications are a recognized risk associated with all anticoagulant use, and clinical vigilance is required to enable effective, rapid bleeding control In phase III clinical trials of 'Xarelto', rates of bleeding were similar to or lower than standard of care. In EINSTEIN PE, rates of major bleeding were reduced by 51% in patients who received 'Xarelto' compared with enoxaparin/VKA6 Several effective approaches are available if bleeding occurs while a patient is receiving 'Xarelto'. These include local compression, surgical intervention, fluid replacement or blood product replacement until haemostasis is restored, along with delay or discontinuation of anticoagulation1,2 An agent is not yet available for specific reversal of 'Xarelto' anticoagulant activity, or for any of the novel oral anticoagulants PCC, activated PCC and recombinant Factor VIIa have all been investigated for the reversal of 'Xarelto' activity in studies involving healthy volunteers with promising results;3,4 however, further studies are still ongoing A universal Factor Xa reversal agent is in development,5 which includes a phase II study in humans (ClinicalTrials.gov identifier: NCT01758432) Abbreviations PCC, prothrombin complex concentrate; VKA, vitamin K antagonist References Siegal DM et al. Eur Heart J 2013;34:489–498b Bauer KA. Am J Hematol 2012;87 Suppl 1:S119–126 Eerenberg ES et al. Circulation 2011;124:1573–1579 Marlu R et al. Thromb Haemost 2012;108:217–224 Lu G et al. Nat Med 2013;19:446–451 The EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–1297 1. Siegal et al, 2012; 2. Bauer KA, 2012; 3. Eerenberg et al, 2012; 4. Marlu et al, 2012; 5. Lu et al, 2013