1. Apixaban in the treatment of DVT/PE Dr Scott Dunkley Institute of Haematology Royal Prince Alfred Hospital, Sydney

2. Before prescribing, please review full Product Information available with this presentation. For further information please go to www.eliquis.com.au Bristol-Myers Squibb and Pfizer abide by the Medicines Australia Code of Conduct and our own internal policies, and as such, will not engage in the promotion of unregistered products or unapproved indications. The statements, conclusions and opinions contained in the following presentations are those of the presenter and do not necessarily reflect those of the sponsor Bristol-Myers Squibb or Pfizer. Please refer to the appropriate approved Product Information before prescribing any agents mentioned in this presentation. The Product Information is available through the BMS Australia and Pfizer Australia websites, the trade display or from your BMS or Pfizer representative. Bristol-Myers Squibb Australia Pty Ltd, ABN 33 004 333 322, Level 2, 4 Nexus Court, Mulgrave, VIC, Australia. Pfizer Australia Pty Ltd, ABN 50 008 422 348 38-42 Wharf Road, West Ryde, NSW, AUSTRALIA. ELI/0627/09-15 September 2015 Disclaimer

3. DVT/PE in Australia 3 * Estimates based on Australian Institute of Health and Welfare hospital separations data, triangulated against Western Australia and overseas data 1,2 1.Access Economics. The burden of venous thromboembolism in Australia, 2008 2.Ho WK et al., Med J Aust 2008; 189:144-47 3.Ho WK et al. Med J Aust 2005; 182:476-481 Before prescribing, please review full Product Information available with this presentation. For further information please go to www.eliquis.com.au

4. Classical Treatment of DVT/PE ACCP 2012 Guidelines: Three Phases of Anticoagulant Initial (0 to ~7 days) Long-Term (~7 days to ~3–6 months) Extended (~3 – 6 months to indefinite#) Heparin, low-molecular-weight heparin (LMWH), fondaparinux (rationale is the half life of F2, F9, F10 vs F7 and protein C and S) # Indefinite / long-term is the real decision point † Includes LMWH, dabigatran, rivaroxaban. ACCP=American College of Chest Physicians. Kearon C et al. Chest. 2012;141(2 suppl):e419S-e494S. 123 4 Adapted from Kearon et al. Vitamin K antagonist (VKA) or other agent † Parenteral*

5. 12345678 Time From Treatment Initiation (Years) 0 10 20 30 40 Cumulative Incidence of DVT/PE (%) The Cumulative Rate of DVT/PE Recurrence Is Approximately 25% at 5 Years The cumulative rate of DVT/PE recurrence in patients with a first-episode DVT was approximately 25% at 5 years and 30% at 8 years *A prospective cohort study of 355 consecutive patients with a first episode of symptomatic DVT measuring recurrent DVT/PE, post-thrombotic syndrome, and death. Prandoni P et al. Ann Intern Med. 1996;125:1-7. In a Prospective Study* of DVT/PE Recurrence in DVT Patients (Italy)

6. Historically longterm anticoagulation prevents recurrence but at the cost of bleeding Kearon et al, NEJM 1999 Major haemorrhage rate of 3.8% per patient year on warfarin Cumulative probability of recurrent VTE after initial three months of warfarin

7. Advantages and Disadvantages of Initial Treatment With Heparins UFH ► Usually given IV, requiring hospitalization 3 ► Monitoring and dose adjustment required 3 ► Major bleeding risk (mean 4.4%; range 0%– 11.5%) during initial treatment (8 days) 5 ► Heparin-induced thrombocytopenia risk 3 LMWH ► Injections: patient/caregiver education 6 ► Major bleeding risk (mean 4.4%; range 0%– 12.5%) during initial treatment (8 days) 5 ► Protamine sulfate only partially reverses 3 ► Heparin-induced thrombocytopenia risk 3 UFH ► Usually given IV, requiring hospitalization 3 ► Monitoring and dose adjustment required 3 ► Major bleeding risk (mean 4.4%; range 0%– 11.5%) during initial treatment (8 days) 5 ► Heparin-induced thrombocytopenia risk 3 LMWH ► Injections: patient/caregiver education 6 ► Major bleeding risk (mean 4.4%; range 0%– 12.5%) during initial treatment (8 days) 5 ► Protamine sulfate only partially reverses 3 ► Heparin-induced thrombocytopenia risk 3 UFH ► Experience since the 1940s 1 ► Rapid onset 2 ► Very short half-life (60–90 min) 3 ► Reversal agent exists (eg, protamine sulfate) 3 LMWH ► Subcutaneous injection (use in outpatients) 3,4 ► Rapid onset (3–5 h) ► Short half-life (3–6 h) 3 ► Monitoring generally not required 3 UFH ► Experience since the 1940s 1 ► Rapid onset 2 ► Very short half-life (60–90 min) 3 ► Reversal agent exists (eg, protamine sulfate) 3 LMWH ► Subcutaneous injection (use in outpatients) 3,4 ► Rapid onset (3–5 h) ► Short half-life (3–6 h) 3 ► Monitoring generally not required 3 DisadvantagesAdvantages IV=intravenously; LMWH=low-molecular-weight heparin; UFH=unfractionated heparin. 1.Büller HR et al. J Thromb Haemost. 2005;3:1554-1560. 2.Mackman N et al. Arterioscler Thromb Vasc Biol. 2010;30:369-371. 3.Garcia DA et al. Chest. 2012;141(2 Suppl):e24S-43S. 4.Goldhaber SZ. Pulmonary Embolism. In: Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 9th ed. Philadelphia, PA: Elsevier, 2012. 5.Costantino G et al. PLoS One. 2012;7:e44553. 6.Colwell CW Jr et al. Orthopedics. 2005;28:143-147. 7.Kearon C et al. JAMA. 2006;296:935-942. 7 Before prescribing, please review full Product Information available with this presentation. For further information please go to www.eliquis.com.au

8. Advantages and Disadvantages of VKA Therapy INR=international normalized ratio; VKA=vitamin K antagonist. 1.van Es J et al. J Thromb Haemost. 2011;9 (Suppl 1):265-274. 2.Ageno W et al. Chest. 2012;141;e44S-e88S. 3.Willey VJ et al. Clin Ther. 2004;26:1149-1159. Disadvantages ► Slow onset; requires (~5–10 days) parenteral bridging 1 ► Regular monitoring required 1 ► Challenging to maintain INRs in therapeutic range 1 Time in range only 37.7% in a US study 3 ► Numerous drug interactions 1 ► Dietary limitations 2 ► Slow onset; requires (~5–10 days) parenteral bridging 1 ► Regular monitoring required 1 ► Challenging to maintain INRs in therapeutic range 1 Time in range only 37.7% in a US study 3 ► Numerous drug interactions 1 ► Dietary limitations 2 Advantages ► Convenience of oral administration 1 ► When used after initial heparin, reduces recurrent DVT/PE 1 ► Vitamin K and pro-coagulants provide options for reversal 2 ► Low drug cost ► Convenience of oral administration 1 ► When used after initial heparin, reduces recurrent DVT/PE 1 ► Vitamin K and pro-coagulants provide options for reversal 2 ► Low drug cost 8

9. Unmet Clinical Needs for DVT/PE Treatment Initial and long-term treatment phases An oral anticoagulant with: – rapid onset (within hours) to eliminate the need for bridging 1 – an improved risk/benefit profile ; similar efficacy with significantly less bleeding compared to standard of care 2 – minimal patient-related inconveniences (eg, routine monitoring, multiple dose adjustments, interactions with drugs or food, and challenges associated with injections ) 1,3 – characteristics that allow more patients to be treated as outpatients, 4 to reduce hospitalization costs and monitoring costs, and to reduce resource utilization compared to standard of care 3,5 1.van Es J et al. J Thromb Haemost. 2011;9(Suppl 1):265-274. 2.Key NS et al. Arterioscler Thromb Vasc Biol. 2010;30:372-375. 3.Hoffman R et al. Best Pract Res Clin Haematol. 2012;25:351-360. 4.Vinson DR et al. Ann Emerg Med. 2012;60:651-662. 5.Hass B et al. Thromb J. 2012;10:24. 9

10. Before prescribing, please review full Product Information available with this presentation. For further information please go to www.eliquis.com.au ELIQUIS Is a Factor Xa (FXa) Inhibitor C max =maximum concentration; TF=tissue factor. 1.Eliquis Product Information, 20 May 2015, Therapeutic Goods Administration, https://www.ebs.tga.gov.au/https://www.ebs.tga.gov.au/ 2.Eliquis Consumer Medicine Information, 20 May 2015, Therapeutic Goods Administration, https://www.ebs.tga.gov.au/https://www.ebs.tga.gov.au/ 3.Melnikova I. Nat Rev Drug Discov. 2009;8:353-354. 4.Granger CB et al. N Engl J Med. 2011;365:981-992. Coagulation Cascade 3,4 Mechanism of action 1,2 ► ELIQUIS is a selective, oral FXa inhibitor 1 ► By inhibiting FXa, ELIQUIS decreases thrombin generation and thrombus development Pharmacokinetic properties 1,2 ► Rapid onset of action ► C max : 3–4 hours after oral administration ► Renal excretion accounts for ~27% of total clearance ► ~12-hour half-life following oral administration Xa Thrombin VIIa TF Direct Factor Xa Inhibitors Fibrinogen Fibrin IXa VIIIa 10

11. Before prescribing, please review full Product Information available with this presentation. For further information please go to www.eliquis.com.au ELIQUIS Has a Demonstrated Efficacy and Safety Profile Across Multiple Indications 1,2 11 ELIQUIS is indicated for the following, in adult patients: ► Prevention of stroke and systemic embolism in patients with NVAF and at least one additional risk factor for stroke. ► Treatment of DVT ► Treatment of PE ► Prevention of recurrent DVT and PE ► Prevention of DVT/PE after elective total knee replacement surgery ► Prevention of DVT/PE after elective total hip replacement surgery NVAF=nonvalvular atrial fibrillation. 1.Eliquis Product Information, 20 May 2015, Therapeutic Goods Administration, https://www.ebs.tga.gov.au/https://www.ebs.tga.gov.au/ 2.Eliquis Consumer Medicine Information, 20 May 2015, Therapeutic Goods Administration, https://www.ebs.tga.gov.au/https://www.ebs.tga.gov.au/

12. Zikria JC. Ansell J. Current Opinion in Hematology 2009;16:347-56. The new drugs…

13. Pharmacokinetic Properties/Profile Supporting Twice-Daily Dosing for ELIQUIS 13 *A double-blind, randomized, multiple ascending dose PK/PD study in healthy subjects. † Not an approved dose of ELIQUIS. 1.Frost C et al. Br J Clin Pharmacol. 2013;76:776-786. 2.Eliquis Product Information, 20 May 2015, Therapeutic Goods Administration, https://www.ebs.tga.gov.au/https://www.ebs.tga.gov.au/ 3.Eliquis Consumer Medicine Information, 20 May 2015, Therapeutic Goods Administration, https://www.ebs.tga.gov.au/https://www.ebs.tga.gov.au/ ► Peak-to-trough ratios for ELIQUIS were lower for the twice-daily vs the once-daily dosing regimens, providing less fluctuation in drug exposure over the dosing interval 1 ► The apparent half-life for ELIQUIS during repeat dosing is about 12 hours 2,3 ► Pharmacokinetic data should not be used to draw conclusions regarding clinical outcomes ELIQUIS Concentration (ng/mL) 250 200 150 100 50 0 Day 7: 06121824 Time (h) Mean Plasma Concentration Following Multiple Oral Doses* 1 5 mg twice daily 10 mg once daily † Before prescribing, please review full Product Information available with this presentation. For further information please go to www.eliquis.com.au

15. ELIQUIS phase III clinical trial mirrored the ACCP treatment stages 1-3 15 1.Eliquis Product Information, 20 May 2015, Therapeutic Goods Administration, https://www.ebs.tga.gov.au/https://www.ebs.tga.gov.au/ 2.Agnelli G et al. N Engl J Med. 2013;369:799-808. 3.Agnelli G et al. N Engl J Med. 2013;368:699-708. AMPLIFY-EXT (N=2482) AMPLIFY (N=5395) Initial Treatment Long-term TreatmentExtended Treatment 7 days6 months18 months

16. ELIQUIS: Overview of AMPLIFY and AMPLIFY-EXT Trial Designs for DVT/PE Treatment and Prevention of Recurrence Major bleeding was defined as clinically overt and associated with a decrease in the hemoglobin level of ≥2 g/dL, required the transfusion of ≥2 units of blood, occurred into a critical site, or contributed to death. INR=international normalized ratio; TTR=time in therapeutic range. 1.Eliquis Product Information, 20 May 2015, Therapeutic Goods Administration, https://www.ebs.tga.gov.au/https://www.ebs.tga.gov.au/ 2.Agnelli G et al. N Engl J Med. 2013;369:799-808. 3.Agnelli G et al. N Engl J Med. 2013;368:699-708.  Clinical diagnosis of DVT or PE  Completed 6- to 12-month anticoagulant treatment (or AMPLIFY), with no recurrence of DVT/PE  Clinical uncertainty regarding the continuation or cessation of anticoagulation therapy  Clinical diagnosis of DVT or PE  Completed 6- to 12-month anticoagulant treatment (or AMPLIFY), with no recurrence of DVT/PE  Clinical uncertainty regarding the continuation or cessation of anticoagulation therapy ELIQUIS 2.5 mg twice daily ELIQUIS 5 mg twice daily Placebo twice daily n=840 n=813 n=829 R R AMPLIFY: Initial and Long-term DVT/PE Treatment 1-3 (N=5395) AMPLIFY-EXT: A 12-Month Extension Trial 1-3 (N=2482) n=2704 n=2691 R R ≥5 days6 months 7 days6 months ELIQUIS 10 mg twice daily, orally ELIQUIS 5 mg twice daily, orally Enoxaparin 1 mg/kg twice daily until INR ≥2.0 Warfarin, INR 2.0–3.0 (mean TTR was 60.9%)  Confirmed symptomatic DVT/PE requiring treatment for ≥6 months  With or without prior parenteral anticoagulation (≤48 hours)  Confirmed symptomatic DVT/PE requiring treatment for ≥6 months  With or without prior parenteral anticoagulation (≤48 hours) 12 months 16 Primary Safety Endpoint: Major bleeding* Primary Safety Endpoint: Major bleeding* Primary Efficacy Endpoint: Recurrent DVT/PE or DVT/PE-related death Primary Efficacy Endpoint: Recurrent DVT/PE or DVT/PE-related death Primary Safety Endpoint: Major bleeding* Primary Safety Endpoint: Major bleeding* Primary Efficacy Endpoint: Recurrent DVT/PE or all-cause death Primary Efficacy Endpoint: Recurrent DVT/PE or all-cause death Before prescribing, please review full Product Information available with this presentation. For further information please go to www.eliquis.com.au

17. Baseline characteristics

18. Compared to Enoxaparin/Warfarin, ELIQUIS Demonstrated Comparable Efficacy 1 Time to DVT/PE or DVT/PE-Related Death (Days) Patients With Recurrent DVT/PE or DVT/PE-Related Death (%) ELIQUIS (events: 59/2609) Enoxaparin/Warfarin (events: 71/2635) 0306090120150180210240270300 0.0 RR (95% CI): 0.84 (0.60, 1.18) P<0.001 (noninferiority) 0.5 1.0 1.5 2.0 2.5 3.0 18 1.Agnelli G et al. N Engl J Med. 2013;369:799-808.

19. Apixaban: Demonstrated Consistency Across Efficacy Results 1 1.Agnelli G et al. N Engl J Med. 2013;369:799-808.

20. ELIQUIS Demonstrated a Significant 69% Relative Risk Reduction in Major Bleeding vs Enoxaparin/Warfarin ELIQUIS Enoxaparin/ Warfarin 1.Agnelli G et al. N Engl J Med. 2013;369:799-808. ELIQUIS (events: 15/2676) Enoxaparin/Warfarin (events: 49/2689) 0306090120150180210240270300 Patients With Major Bleeding (%) 0.0 0.5 1.0 1.5 2.0 267625192460240923732339614100 268924882426238323392310433110 Number of Subjects at Risk 69% RRR Time to Major Bleeding (Days) 20 RR (95% CI): 0.31 (0.17, 0.55) P<0.001 (superiority) Before prescribing, please review full Product Information available with this presentation. For further information please go to www.eliquis.com.au

21. APIXABAN Demonstrated Reduced Bleeding Across All Protocol-Defined Bleeding Endpoints 1

22. Comparison of PREVENT and ELATE Full dose Warfarin was better at prevention Low dose Warfarin had the same bleeding Low dose Warfarin failed to show a benefit PREVENT Trial. Ridker PM, et al. NEJM 2003; 348: 1425-34. ELATE trial. Kearon C, et al. NEJM 2003; 349: 631-39.

24. Agnelli G, et al. NEJM 2013 Prevention of recurrent DVT/PE with apixaban

25. Agnelli G, et al. NEJM 2013 Bleeding rates Placebo vs apixaban 2.5mg BD vs 5mg BD

26. Bleeding rates were reduced across all subgroups 1 Agnelli G, et al. NEJM 2013

27. No Significant difference Incidence of Major Bleeding : REDUCED 67% RRR Recurrent DVT/PE or All-Cause Death Agnelli G et al. N Engl J Med. 2013;368:699-708 12-Month Extension Trial Apixaban 2.5 mg BID: Superior to Placebo in Reducing Risk of VTE Recurrence, With a Major Bleeding Incidence Similar to Placebo 1

28. ELIQUIS 5 mg BID* Was Superior to Placebo in Reducing Risk of VTE Recurrence, With a Major Bleeding Incidence Similar to Placebo 1-2 12-Month Extension Trial 28 ► ELIQUIS 5 mg BID demonstrated efficacy across subgroups that was generally consistent with the overall results of the trial; subgroups included age, sex, BMI, and renal function Primary Efficacy Endpoint: SUPERIOR 64% RRR Recurrent DVT/PE or All-Cause Death P<0.001 Primary Safety Endpoint: SIMILAR Incidence of Major Bleeding RR (95% CI): 0.25 (0.03–2.24) * The recommended dose for of ELIQUIS for prevention of recurrent DVT/PE is 2.5mg BD after at least 6 months of treatment for DVT/PE 1 ELIQUIS 5-mg BID data not shown; BID=twice daily. 1.Eliquis Product Information, Therapeutic Goods Administration, 20 May 2015, https://www.ebs.tga.gov.au/https://www.ebs.tga.gov.au/ 2.Agnelli G et al. N Engl J Med. 2013;368:699-708. P=not significant

29. Before prescribing, please review full Product Information available with this presentation. For further information please go to www.eliquis.com.au ELIQUIS: Dosing ► ELIQUIS has a rapid onset of action, eliminating the need for injectable LMWH therapy during initiation 2 ► ELIQUIS has no known dietary restrictions and can be taken with or without food 1 Only ELIQUIS offers a short, 7-day treatment initiation period for DVT/PE treatment and a lower dose for extended therapy 1,2 BID=twice daily; LMWH=low-molecular-weight heparin. 1.Eliquis Product Information, Therapeutic Goods Administration, 20 May 2015, https://www.ebs.tga.gov.au/https://www.ebs.tga.gov.au/ 2.Yamahira N et al. Int J Clin Pharmacol Ther. 2014. doi:10.5414/CP201967. 29 AMPLIFY-EXT AMPLIFY Initiation Long-term therapy Extended therapy 7 days≥6 months 10 mg BID 5 mg BID 2.5 mg BID

30. Before prescribing, please review full Product Information available with this presentation. For further information please go to www.eliquis.com.au Renal ► In patients with mild or moderate renal impairment, no dose adjustment is necessary ► As there is no clinical experience in patients with renal impairment <15 mL/min or in patients undergoing dialysis, ELIQUIS is contraindicated in these patients. There is limited experience in patients with renal impairment 15 mL to <25 mL/min with increased apixaban exposure, therefore ELIQUIS is also contraindicated in these patients. Hepatic ► ELIQUIS is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including severe hepatic impairment (Child-Pugh C) ► ELIQUIS may be used with caution in patients with mild or moderate hepatic impairment (Child-Pugh A or B) ► Patients with elevated liver enzymes (ALT/AST >2x ULN) or total bilirubin ≥1.5x ULN were excluded from clinical trials Therefore, ELIQUIS should be used cautiously in this population Prior to initiating ELIQUIS, liver function testing should be performed 30 1.Eliquis Product Information, 20 May 2015, Therapeutic Goods Administration, https://www.ebs.tga.gov.au/https://www.ebs.tga.gov.au/ House keeping !!

31. Guidance for Switching Patients to and From ELIQUIS 1 31 PatientsRecommendation SWITCHING from parenteral anticoagulant or another NOAC to ELIQUIS Discontinue therapy and start ELIQUIS twice daily at the next scheduled dose SWITCHING from warfarin or other VKA to ELIQUIS Discontinue warfarin or other VKA and start ELIQUIS twice daily when INR is <2.0 SWITCHING from ELIQUIS to VKA Continue administration of ELIQUIS for ≥ 2 days after beginning VKA therapy. After 2 days of co-administration of ELIQUIS with VKA therapy, obtain an INR prior to the next scheduled dose of ELIQUIS. Continue co-administration of ELQIUIS and VKA therapy until the INR is ≥ 2.0. ELIQUIS affects INR; therefore, initial INR measurements during the transition to warfarin may not be useful for determining the appropriate dose of warfarin INR=international normalized ratio; NOAC=novel oral anticoagulant; VKA=vitamin K antagonist. 1.Eliquis Product Information, 20 May 2015, Therapeutic Goods Administration, https://www.ebs.tga.gov.au/https://www.ebs.tga.gov.au/ Before prescribing, please review full Product Information available with this presentation. For further information please go to www.eliquis.com.au

32. ELIQUIS: Temporary Interruption for Surgery and Other Interventions 1,2 1.Eliquis Product Information, 20 May 2015; 2.Ward et al. Thrombosis J 2013; 11:27 32 Bleeding risk with elective surgery or invasive proceduresRecommendation Moderate or high risk of unacceptable or clinically significant bleeding Discontinue ELIQUIS at least 48 hours prior Low risk or noncritical site and easily controlled Discontinue ELIQUIS at least 24 hours prior Before prescribing, please review full Product Information available with this presentation. For further information please go to www.eliquis.com.au

33. Why Apixaban ? Apart from the fact it works well and has a low bleeding rate Short and oral initiation phase Compliance / forget a tablet ? Less dependent upon renal function PK profile – peaks (bleeding) + troughs (recurrence) “have your cake and eat it to” ? (2.5mg BD)

34. Summary Apixaban is effective in treating acute DVT and PE Bleeding rates are dramatically reduced cf with LMWH/Warfarin, including major bleeding and ICH Patient selection remains important On going treatment with apixaban prevents recurrence With a low cumulative rate of bleeding Long-term therapy with 2.5mg BD appears to have a very low bleed risk whilst maintaining efficacy Thankyou for your attention