UK/CVS (1) | February 2013 Emerging technologies for stroke prevention in atrial fibrillation UK/CVS (1) | Date of preparation: February 2013 Developed and funded by Clinical trial data indirect comparisons Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. Summary of Product Characteristics for rivaroxaban (Xarelto® ) can be found at: Xarelto 20 mg: Xarelto 15 mg: Summary of Product Characteristics for dabigatran etexilate (Pradaxa®) can be found at: Pradaxa 150 mg: Pradaxa 110 mg: Summary of Product Characteristics for apixaban (Eliquis® ) can be found at: Eliquis 5.0 mg: Eliquis 2.5 mg:

UK/CVS (1) | February 2013 Emerging technologies for stroke prevention in atrial fibrillation Clinical trial data indirect comparisons Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. Summary of Product Characteristics for rivaroxaban (Xarelto® ) can be found at: Xarelto 20 mg: Xarelto 15 mg: Summary of Product Characteristics for dabigatran etexilate (Pradaxa®) can be found at: Pradaxa 150 mg: Pradaxa 110 mg: Summary of Product Characteristics for apixaban (Eliquis® ) can be found at: Eliquis 5.0 mg: Eliquis 2.5 mg:

UK/CVS (1) | February 2013 Clinical data indirect comparisons No direct head-to-head clinical trials comparing the novel oral agents have been conducted to date The following data for the novel agents has been presented using warfarin as the common comparator Please note that differences exist across trial design and patient populations studied Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information.

UK/CVS (1) | February 2013 Pharmacology 1. Ezekowitz MD et al. Am Heart J 2009;157:805–10; 2. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 3. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 4. Rocket Investigators. Am Heart J 2010;159: ; 5. Patel MR et al. NEJM 2011;365:883–91; 6. Lopes et al. Am Heart J 2010;159:331-9; 7. Granger et al. N Eng J Med 2011;365: Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. Dabigatran1-3Rivaroxaban4,5Apixaban6,7 Mode of actionFactor IIFactor X Half life12-14 hrs7-11 hrs12 hrs Dosing (in atrial fibrillation) B.D.O.D.B.D. Metabolism Esterase catalysed hydrolysis CYP P450 dependant and independent mechanisms CYP P450 Excretion80% Renal 1/3 Renal 2/3 Hepatic 1/4 Renal 3/4 Non Renal FormCapsuleTablet Dose 150 mg 110 mg (>80 yrs, verapamil or increased bleeding risk) 20 mg 15 mg (CrCL ml/min) 5 mg 2.5 mg (2 or more: >80yr; weight <60 kg; Cr >1.5 mg/dL) B.D. = twice daily; O.D. = once daily

UK/CVS (1) | February 2013 SPAF trials versus warfarin 1. Ezekowitz MD et al. Am Heart J 2009;157:805–10; 2. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 3. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 4. Rocket Investigators. Am Heart J 2010;159: ; 5. Patel MR et al. NEJM 2011;365:883–91; 6. Lopes et al. Am Heart J 2010;159:331-9; 7. Granger et al. N Eng J Med 2011;365: Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. Dabigatran1-3Rivaroxaban4,5Apixaban6,7 StudyRE-LYROCKET-AFARISTOTLE DesignPROBEDouble Blind Follow up2 yrs1.5 yrs Population size>18,000>14,000>18,000 Inclusion Nonvalvular AF + 1 risk factor Nonvalvular AF + 2 risk factors (i.e. moderate to high risk) Nonvalvular AF + 1 risk factor Inclusion (CHADS) Primary Endpoint Stroke and systemic embolism Warfarin comparator INR control (mean TTR) 64%55%62% PROBE = prospective randomised open blinded end-point; INR = international normalised ratio; TTR = time in therapeutic range

UK/CVS (1) | February 2013 Dabigatran 110 mg vs Warfarin (D110 N=6015) Dabigatran 150 mg vs Warfarin (D150 N=6076) Warfarin (N=6022) D110 # D110 %/yr ARRHRP = D150 # D150 %/yr ARRHRP = Warf # Warf %/yr Stroke or systemic embolism (sup) <0.001 (sup) RE-LY: Stroke, systemic embolism* Connolly SJ et al. N Engl J Med 2009;361:1139–51. Connolly SJ et al. N Engl J Med 2010;363:1875–6. Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. Fig: Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism, According to Treatment Group RE-LY: The primary endpoint was stroke or systemic embolism. *Intention-to-Treat population

UK/CVS (1) | February 2013 RE-LY: Stroke (ischaemic, haemorrhagic, disabling or fatal)* Connolly SJ et al. N Engl J Med 2009;361:1139–51. Connolly SJ et al. N Engl J Med 2010;363:1875–6. Pradaxa® 150 mg hard capsules Summary of Product Characteristics. Available at Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. Dabigatran 110 mg vs Warfarin (D110 N=6015) Dabigatran 150 mg vs Warfarin (D150 N=6076) Warfarin (N=6022) D110 # D110 %/yr ARRHRP = D150 # D150 %/yr ARRHRP = Warf # Warf %/yr Ischaemic stroke Haemorrhagic stroke < < Disabling or fatal stroke *Intention-to-Treat population

UK/CVS (1) | February 2013 RE-LY: Myocardial infarction, vascular mortality, all cause mortality* Connolly SJ et al. N Engl J Med 2009;361:1139–51. Connolly SJ et al. N Engl J Med 2010;363:1875–6. Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. Dabigatran 110 mg vs Warfarin (D110 N=6015) Dabigatran 150 mg vs Warfarin (D150 N=6076) Warfarin (N=6022) D110 # D110 %/yr ARRHRP = D150 # D150 %/yr ARRHRP = Warf # Warf %/yr Myocardial infarction Vascular mortality All cause mortality *Intention-to-Treat population

UK/CVS (1) | February 2013 RE-LY: Safety endpoints* Connolly SJ et al. N Engl J Med 2009;361:1139–51. Connolly SJ et al. N Engl J Med 2010;363:1875–6. Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. Dabigatran 110 mg vs Warfarin (D110 N=6015) Dabigatran 150 mg vs Warfarin (D150 N=6076) Warfarin (N=6022) D110 # D110 %/yr ARRHRP = D150 # D150 %/yr ARRHRP = Warf # Warf %/yr Major Bleeding (sup) (sup) Gastro- intestinal bleeding Intracranial bleeding < < Any bleeding† < RELY: Major bleeding was defined as a reduction in the haemoglobin level of at least 20 g per litre, transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ. Life-threatening bleeding was a subcategory of major bleeding that consisted of fatal bleeding, symptomatic intracranial bleeding, bleeding with a decrease in the haemoglobin level of at least 50 g per litre, or bleeding requiring transfusion of at least 4 units of blood or inotropic agents or necessitating surgery. All other bleeding was considered minor. *Intention-to-Treat population, †Any bleeding = major and minor bleeding

UK/CVS (1) | February 2013 ROCKET-AF: Stroke, systemic embolism Patel MR et al. NEJM 2011;365:883–91 and Supplementary Appendix. Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. Rivaroxaban (SAT N=7061, ITT N=7081) Warfarin (SAT N=7082, ITT N=7090) Rivaroxaban vs Warfarin Stroke, systemic embolism # No. / 100 pts yrs # No. / 100 pts yrs ARRHRP = Safety, as treated (SAT) ( )0.02 (sup) Intention to treat (ITT) ( )0.12 (sup) Fig: Cumulative Rates of the Primary End Point (Stroke or Systemic Embolism) in the Intention-to-Treat Population ROCKET-AF: The primary efficacy end point was the composite of stroke (ischaemic or haemorrhagic) and systemic embolism.

UK/CVS (1) | February 2013 ROCKET-AF: Stroke (ischaemic, haemorragic, disabling, fatal) Patel MR et al. NEJM 2011;365:883–91 and Supplementary Appendix. Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. Rivaroxaban (N=7061) Warfarin (N=7082) Rivaroxaban vs Warfarin # No. / 100 pts yrs # No. / 100 pts yrs ARRHRP = Ischaemic stroke Haemorrhagic stroke Disabling stroke Fatal stroke Based on Safety on Treatment population

UK/CVS (1) | February 2013 ROCKET-AF: Myocardial infarction, vascular mortality, all cause mortality Patel MR et al. NEJM 2011;365:883–91 and Supplementary Appendix. Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. Rivaroxaban (N=7061) Warfarin (N=7082) Rivaroxaban vs Warfarin # No. / 100 pts yrs # No. / 100 pts yrs ARRHRP = Myocardial infarction Vascular mortality All cause mortality Based on Safety on Treatment population

UK/CVS (1) | February 2013 ROCKET-AF: Safety endpoints Patel MR et al. NEJM 2011;365:883–91 and Supplementary Appendix. Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. Rivaroxaban (N = 7111) Warfarin (N=7125) Rivaroxaban vs Warfarin # (%)%/yr# (%)%/yrARRHR (95% CI)P= Major bleeding395 (5.6) (5.4) ( )0.58 Gastrointestinal bleeding 224 (3.2)n/a154 (2.2)n/a n/a*<0.001 Intracranial bleeding 55 (0.8)0.584 (1.2) ( )0.02 Any bleeding†1475 (20.7) (20.3) ( )0.44 *HR and 95% CI not available in publication, †Any bleeding = major and non-major clinically relevant bleeding (excludes minimal bleeding) Based on Safety on Treatment Population. ROCKET AF: Major bleeding was defined as clinically overt bleeding associated with any of the following: fatal outcome, involvement of a critical anatomic site (intracranial, spinal, ocular, pericardial, articular, retroperitoneal, or intramuscular with compartment syndrome), fall in haemoglobin concentration ≥2 g/dL, transfusion of ≥2 units of whole blood or packed red blood cells, or permanent disability.

UK/CVS (1) | February 2013 ARISTOTLE: Stroke, systemic embolism* Granger et al. N Eng J Med 2011;365: Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. Apixaban (N=9120) Warfarin (N=9081) Apixaban vs Warfarin #%/yr# ARRHRP = Stroke, systemic embolism (sup) ARISTOTLE: The primary endpoint was ischaemic or haemorrhagic stroke or systemic embolism. *Intention-to-Treat population

UK/CVS (1) | February 2013 ARISTOTLE: Stroke (ischaemic or uncertain, haemorrhagic, disabling or fatal)* Granger et al. N Eng J Med 2011;365: Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. Apixaban (N=9120) Warfarin (N=9081) Apixaban vs Warfarin #%/yr# ARRHRP = Ischaemic or uncertain stroke Haemorrhagic stroke <0.001 Disabling or fatal stroke n/a† †p-value not available in publication. *Intention-to-Treat population

UK/CVS (1) | February 2013 ARISTOTLE: Myocardial infarction, vascular mortality, all cause mortality* Granger et al. N Eng J Med 2011;365: Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. Apixaban (N=9120) Warfarin (N=9081) Apixaban vs Warfarin #%/yr# ARRHRP = Myocardial infarction Vascular mortality† n/a ‡ 1.80 n/a ‡ n/a ‡ All cause mortality †Cardiovascular mortality; ‡p-value not available in publication. *Intention-to-Treat population

UK/CVS (1) | February 2013 ARISTOTLE: Safety endpoints* Granger et al. N Eng J Med 2011;365: Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. Apixaban (N=9088) Warfarin (N=9052) Apixaban vs Warfarin #%/yr# ARRHRP = Major bleeding ( )<0.001 Gastrointestinal bleeding ( )0.37 Intracranial bleeding ( )<0.001 Any bleeding ( )<0.001 ARISTOTLE: Major bleeding, which was defined, according to the ISTH criteria, as clinically overt bleeding accompanied by a decrease in the haemoglobin level of at least 2 g per decilitre or transfusion of at least 2 units of packed red cells, occurring at a critical site, or resulting in death. *Intention-to-Treat population

UK/CVS (1) | February 2013 Novel agents: Stroke, systemic embolism vs warfarin SSE vs warfarin (ITT population) %/yr Warfarin %/yr HR (95% CI) Dabigatran 150 mg ( ) Dabigatran 110 mg ( ) Rivaroxaban ( ) Apixaban ( ) 1. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 3. Patel MR et al. NEJM 2011;365:883–91 and Supplementary Appendix; 4. Granger et al. N Eng J Med 2011;365: Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. Favours novel orals Favours warfarin SSE = stroke and systemic embolism

UK/CVS (1) | February 2013 Novel agents: Ischaemic stroke vs warfarin Ischaemic stroke vs warfarin %/yr Warfari n %/yr HR (95% CI) Dabigatran 150 mg ( ) Dabigatran 110 mg ( ) Rivaroxaban ( ) Apixaban* ( ) Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. 1. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 3. Patel MR et al. NEJM 2011;365:883–91 and Supplementary Appendix; 4. Granger et al. N Eng J Med 2011;365: Favours novel orals Favours warfarin 1. 5 *Ischaemic or uncertain type of stroke

UK/CVS (1) | February 2013 Novel agents: Haemorrhagic stroke vs warfarin Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. 1. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 3. Patel MR et al. NEJM 2011;365:883–91 and Supplementary Appendix; 4. Granger et al. N Eng J Med 2011;365: Favours novel orals Favours warfarin Haemorrhagic stroke vs warfarin %/yr Warfarin %/yr HR (95% CI) Dabigatran 150 mg ( ) Dabigatran 110 mg ( ) Rivaroxaban ( ) Apixaban ( )

UK/CVS (1) | February 2013 Novel agents: Disabling or fatal stroke vs warfarin Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information Connolly SJ et al. N Engl J Med 2009;361:1139–51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 3. Patel MR et al. NEJM 2011;365:883–91 and Supplementary Appendix; 4. Granger et al. N Eng J Med 2011;365: Favours novel orals Favours warfarin Disabling or fatal stroke vs warfarin %/yr Warfarin %/yr HR (95% CI) Dabigatran 150 mg ( ) Dabigatran 110 mg (0.72 ‐ 1.21) Rivaroxaban* Disab ( ) Fatal ( ) Apixaban ( ) * Disabling and fatal stroke reported separately 1. 5

UK/CVS (1) | February 2013 Novel agents: Myocardial infarction vs warfarin Connolly SJ et al. N Engl J Med 2009;361:1139–51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 3. Patel MR et al. NEJM 2011;365:883–91 and Supplementary Appendix; 4. Granger et al. N Eng J Med 2011;365: Favours novel orals Favours warfarin Myocardial infarction vs warfarin %/yr Warfarin %/y r HR (95% CI) Dabigatran 150 mg ( ) Dabigatran 110 mg ( ) Rivaroxaban ( ) Apixaban ( ) Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information.

UK/CVS (1) | February 2013 Novel agents: Vascular mortality vs warfarin 1. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 3. Patel MR et al. NEJM 2011;365:883–91 and Supplementary Appendix; 4. Granger et al. N Eng J Med 2011;365: Vascular mortality vs warfarin %/yr Warfarin %/yr HR (95% CI) Dabigatran 150 mg ( ) Dabigatran 110 mg ( ) Rivaroxaban ( ) Apixaban* ( ) Favours novel orals Favours warfarin 1. 5 * Cardiovascular mortality Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information.

UK/CVS (1) | February 2013 Novel agents: All cause mortality vs warfarin Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. 1. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 3. Patel MR et al. NEJM 2011;365:883–91 and Supplementary Appendix; 4. Granger et al. N Eng J Med 2011;365: All cause mortality vs warfarin %/yr Warfarin %/yr HR (95% CI) Dabigatran 150 mg ( ) Dabigatran 110 mg ( ) Rivaroxaban ( ) Apixaban ( ) Favours novel orals Favours warfarin 1. 5

UK/CVS (1) | February 2013 Novel agents: Major bleeding vs warfarin Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. 1. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 3. Patel MR et al. NEJM 2011;365:883–91 and Supplementary Appendix; 4. Granger et al. N Eng J Med 2011;365: Favours novel orals Favours warfarin Major bleeding vs warfarin %/yr Warfarin %/yr HR (95% CI) Dabigatran 150 mg ( ) Dabigatran 110 mg ( ) Rivaroxaban ( Apixaban ( ) 1. 5

UK/CVS (1) | February 2013 Novel agents: Gastrointestinal major bleeding vs warfarin Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. 1. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 3. Nessel C et al. Chest 2012;142(4):84A. 4. Granger et al. N Eng J Med 2011;365: Gastrointestinal major bleeding vs warfarin %/yr Warfarin %/yr HR (95% CI) Dabigatran 150 mg ( ) Dabigatran 110 mg ( ) Rivaroxaban ( ) Apixaban (0.70–1.15) Favours novel orals Favours warfarin

UK/CVS (1) | February 2013 Novel agents: Intracranial bleeding vs warfarin Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. 1. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 3. Patel MR et al. NEJM 2011;365:883–91 and Supplementary Appendix; 4. Granger et al. N Eng J Med 2011;365: Intracranial bleeding vs warfarin %/yr Warfarin %/yr HR (95% CI) Dabigatran 150 mg ( ) Dabigatran 110 mg ( ) Rivaroxaban ( ) Apixaban ( ) Favours novel orals Favours warfarin

UK/CVS (1) | February 2013 Novel agents: Any bleeding vs warfarin Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information Connolly SJ et al. N Engl J Med 2009;361:1139–51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 3. Patel MR et al. NEJM 2011;365:883–91 and Supplementary Appendix; 4. Granger et al. N Eng J Med 2011;365: Favours novel orals Favours warfarin Any bleeding vs warfarin %/yr Warfarin %/yr HR (95% CI) Dabigatran 150 mg ( ) Dabigatran 110 mg ( ) Rivaroxaban* ( ) Apixaban ( ) 1.5 * major and non-major clinically relevant bleeding (excludes minimal bleeding)

UK/CVS (1) | February 2013 Novel Agents Prescriber guides and adverse event reporting

UK/CVS (1) | February 2013 An educational pack has been developed to support the prescribing of dabigatran etexilate for stroke prevention in nonvalvular atrial fibrillation Go to where you will be able to download the Pradaxa® Educational Packwww.pradaxa.co.uk The pack contains: – Prescriber guide – Summaries of Product Characteristics (SPC) – Patient alert card To order a copy, call the Pradaxa® information line on Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Boehringer Ingelheim Drug Safety on (Freephone) Dabigatran etexilate – educational pack and prescriber guide and adverse event reporting 30 Summary of Product Characteristics for dabigatran etexilate (Pradaxa®) can be found at: Pradaxa 150 mg: Pradaxa 110 mg:

UK/CVS (1) | February 2013 A prescriber guide has been developed to support the prescribing of rivaroxaban for stroke prevention in nonvalvular atrial fibrillation Go to to download the following: – Prescriber guide – Summaries of Product Characteristics (SPC) – Patient alert card Adverse events should be reported. Reporting forms and information can be found at Adverse events should be also be reported to Bayer plc, on tel: , fax: , Rivaroxaban – prescriber guide and adverse event reporting 31 Summary of Product Characteristics for rivaroxaban (Xarelto® ) can be found at: Xarelto 20 mg: Xarelto 15 mg:

UK/CVS (1) | February 2013 A prescriber guide has been developed to support the prescribing of apixaban for stroke prevention in nonvalvular atrial fibrillation Go to to download the following: – Prescriber guide – Summaries of Product Characteristics (SPC) – Patient alert card Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Bristol-Myers Squibb Pharmaceuticals Ltd, Medical Information on , Apixaban – prescriber guide and adverse event reporting 32 Summary of Product Characteristics for apixaban (Eliquis® ) can be found at: Eliquis 5.0 mg: Eliquis 2.5 mg: