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Stroke prevention in atrial fibrillation: current limitations and novel antithrombotic agents Module 5.

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Presentation on theme: "Stroke prevention in atrial fibrillation: current limitations and novel antithrombotic agents Module 5."— Presentation transcript:

1 Stroke prevention in atrial fibrillation: current limitations and novel antithrombotic agents Module 5

2 Limitations of current antithrombotic agents

3 3 Limitations of current treatment options for stroke prevention in AF Many patients with AF do not receive effective thromboprophylaxis due to limitations of currently available agents Aspirin is convenient to use but provides insufficient protection for stroke prevention in high-risk patients 1 Vitamin K antagonists have greater efficacy but a range of limitations make them challenging agents to use: 2,3 –Narrow therapeutic window –Variable and unpredictable pharmacokinetics and pharmacodynamics –Wide variety of drug–drug and drug–food interactions –Need for regular anticoagulation monitoring and dose adjustments –Slow onset and offset of action 1. ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354 & Eur Heart J 2006;27:1979–2030; 2. Turpie AG. Eur Heart J 2008;29:155–65; 3. Khoo CW et al. Int J Clin Pract 2009;63:630–41

4 Intracerebral haemorrhage: the most feared complication of antithrombotic therapy >10% of intracerebral haemorrhages occur in patients on antithrombotic therapy Intracerebral haemorrhages during anticoagulation can be life-threatening Compared with placebo, antithrombotic therapy increases the risk of intracerebral haemorrhage: –~40% with Aspirin –~200% with warfarin (INR 2.0–3.0; increases to 0.3–0.6%/year) 4 Hart RG et al. Stroke 2005;36:1588–93 INR = international normalized ratio

5 5 The VKA, warfarin, is used in only half of eligible patients with AF Warfarin use in eligible patients (%) Overall use = 55% Age (yrs) 100 < –6465–7475–84  85 44% 58% 61% 57% 35% Go A et al. Ann Intern Med 1999;131:927 Under-use of warfarin is greatest in elderly patients who are at the highest risk of stroke VKA = vitamin K antagonist Figure reproduced with permission: ©2007, American College of Physicians

6 Therapeutic range 1 International normalized ratio Odds ratio VKAs have a narrow therapeutic window ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354 & Eur Heart J 2006;27:1979–2030 Stroke Intracranial bleed VKAs = vitamin K antagonists Graph reproduced with permission: ©2010 American College of Chest Physicians

7 7 Management of AF in clinical practice: prescription of VKAs in eligible patients n = ATRIA cohort (managed care system, California, USA) 3 n = 5333 EuroHeart survey 2 n = Medicare cohort, USA 1 VKAs No anticoagulation 1. Birman-Deych E et al. Stroke 2006;37:1070–4; 2. Nieuwlaat R et al. Eur Heart J 2005;26:2422–34; 3. Go AS et al. JAMA 2003;290:2685–92 Treatment received: 64% 67% 55% VKAs = vitamin K antagonists; ATRIA = Anticoagulation and Risk Factors in Atrial Fibrillation

8 8 The INR for VKAs is often outside the therapeutic range: international study of anticoagulation management Time in target range (%) USACanadaFrance Italy Spain INR <2.0INR 2.0–3.0 INR >3.0 Ansell J et al. J Thromb Thrombolysis 2007;23:83–91 The predominant vitamin K antagonist (VKA) in use was warfarin in the US, Canada and Italy; acenocoumarol in Spain; and fluindione in France; INR = international normalized ratio

9 9 Drug and food interactions associated with an increased potency of VKAs Holbrook AM et al. Arch Intern Med 2005;165:1095–106; du Breuil AL & Umland EM. Am Fam Physician 2007;75:1031–42 Drug/foodExamples AnalgesicsAcetaminophen, propoyphene, salicylates Anti-arrhythmicsAmiodarone, propafenone, quinidine AntibioticsCiprofloxacin, erythromycin, metronidazole AntifungalsFluconazole, itraconazole, miconazole Beta-blockersPropranolol H 2 -receptor antagonists/PPIsCimetidine, omeprazole Lipid-lowering agentsLovastatin, atorvastatin Herbal products/dietary supplementsVitamin E, garlic, devil’s claw MiscellaneousAlcohol (if concomitant liver disease) PPIs = proton pump inhibitors; VKAs = vitamin K antagonists

10 10 Drug and food interactions associated with a reduced potency of VKAs Holbrook AM et al. Arch Intern Med 2005;165:1095–106; du Breuil AL & Umland EM. Am Fam Physician 2007;75:1031–42 Drug/foodExamples AntibioticsDicloxacillin, nafcillin, rifampicin AntifungalsGriseofulvin ImmunosupressantsAzathioprine, cyclosporine Lipid-lowering agentsCholestyramine Herbal products/dietary supplements Coenzyme Q10, ginseng, St John’s wort Foods Green tea, avocados (large amounts), food with high vitamin K content including broccoli and spinach MiscellaneousCarbamazepine, sucralfate, trazodone VKAs = vitamin K antagonists

11 11 VKAs require regular anticoagulation monitoring Careful monitoring of patients being treated with VKAs is critical due to the: –Narrow therapeutic window –Unpredictable relationship between VKA dose and the anticoagulant response –Influence of the quantity of vitamin K in the diet that can change over time Availability of small devices capable of measuring INR enables patients to self-monitor –Reduces risk of thromboembolism and bleeding complications 1 –Increases time in the therapeutic range 2 –Improves patient compliance, treatment satisfaction and quality of life 2,3 –Conflicting evidence on whether it may be more cost-effective 2–4 1. Heneghan C et al. Lancet 2006;367:404–11; 2. Levi M. Expert Rev Cardiovasc Ther 2008;6:979–85; 3. Braun S et al. Anal Bioanal Chem 2009;393:1463–71; 4. Connock M et al. Health Technol Assess 2007;11:iii–66 INR = international normalized ratio; VKAs = vitamin K antagonists

12 12 Contraindications to VKA treatment ACCP Guidelines, 2008: Signer DE et al. Chest 2008;133;546S–92S; Coumadin: SmPC, 2009; Sudlow M et al. Lancet 1998;352:1167–71; Brass LM et al. Stroke 1997;28:2382–9; Kalra L et al. Stroke 1999;30:1218–22; Go AS et al. Ann Intern Med 1999;131:927–34 PregnancyFrequent falls or seizures Coagulation factor abnormalitiesPoor drug or clinic compliance Thrombocytopenia (< /  L) Poorly controlled hypertension (>180/110 mmHg) Haemorrhagic strokeSevere hepatic or renal disease Excessive alcohol intake Threatened abortion (eclampsia, pre-eclampsia) DementiaNon-steroidal agents Recent or contemplated surgery of the CNS or the eye Gastrointestinal or urinary bleeding in the previous 6 months CNS = central nervous system; VKA = vitamin K antagonist

13 13 Many patients with AF are unsuitable for treatment with VKAs 43% 38% 37% 17% 1. Sudlow M et al. Lancet 1998;352:1167–71; 2. Brass LM et al. Stroke 1997;28:2382–9; 3. Kalra L et al. Stroke 1999;30:1218–22; 4. Go AS et al. Ann Intern Med 1999;131:927–34 The contraindications that make patients unsuitable for VKAs are found most frequently in elderly patients who are often at the greatest risk of stroke VKAs = vitamin K antagonists Patients unsuitable for VKAs (%) 50 >65 yrs 1 >65 yrs 2 >75 yrs 3 All ages

14 14 VKAs have a slow onset and offset of action VKAs inhibit the vitamin K-dependent synthesis of clotting factors –Takes several days for functional clotting factors to be cleared from the circulation as well as new factors to be synthesized The initial effect of warfarin administration is to briefly promote clot formation –Warfarin initially decreases the levels of protein S, which is a cofactor for the natural anticoagulant, protein C, resulting in a paradoxical increase in the tendency of the blood to clot The time lag between dosing and the anticoagulant response complicates dose titration to achieve a therapeutic INR Slow offset of action presents a problem if patients experience trauma or require emergency surgery –Persistent anticoagulant activity may increase the risk of bleeding complications Connolly SJ et al. Circulation 2007;116:449–55; Connock M et al. Health Technol Assess 2007;11:iii–66 INR = international normalized ratio; VKAs = vitamin K antagonists

15 15 Requirements of new antithrombotic agents At least as effective as warfarin Predictable response Wide therapeutic window Low incidence and severity of adverse effects Oral fixed dose No need for routine anticoagulation monitoring Low potential for food or drug interactions Fast onset and offset of action Cost-effective Adapted from Lip GY et al. EHJ Suppl 2005;7:E21–5

16 16 Summary: VKAs have many limitations Many AF patients (~50%) do not receive thromboprophylaxis due to the contraindications and limitations associated with current agents, particularly warfarin VKAs have a narrow therapeutic range, requiring regular anticoagulation monitoring for adequate stroke protection, while minimizing the risk of bleeding complications  New antithrombotic therapies are needed, which do not share the limitations of warfarin, to deliver reliable stroke protection to a greater proportion of patients with AF VKAs = vitamin K antagonists

17 Mechanism of action of new antithrombotic agents

18 18 Targets for novel antithrombotic agents in the coagulation cascade 1 1. Adapted from Turpie AG. Eur Heart J 2008;29:155–65; 2. Ellis DJ et al. Circulation 2009;22:120:1029–35; 3. Bousser MG et al. Lancet 2008;371:315–21; 4. NCT ; available at accessed Sept 09; 5. Lopes RD et al. Am Heart J 2010;159:331–9; 6. Eikelboom JW et al. Am Heart J 2010;159:348–53; 7. ROCKET-AF Study Investigators. Am Heart J 2010;159:340–47; 8. NCT ; available at accessed Sept 09; 9. NCT ; available at accessed Sept 09; 10. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 11. Olsson SB et al. Lancet 2003;362:1691–8; 12. Albers GW et al. JAMA 2005;293:690–8; 13. Lip GY et al. Eur Heart J 2009;30:2897–907 AT= antithrombin; Ph = Phase Fibrin IX IXa X VIIIa Thrombin Fibrinogen Direct factor Xa inhibitors: Apixaban (Ph III ongoing) 5,6 Rivaroxaban (Ph III ongoing) 7 Edoxaban (Ph III ongoing) 8 Betrixaban (Ph II ongoing) 9 Va Xa II AT Direct thrombin inhibitors: Dabigatran etexilate (Ph III completed) 10 Ximelagatran (withdrawn 2006) 11,12 AZD0837 (Ph II completed) 13 Indirect factor Xa inhibitors: Idraparinux (Ph III terminated) 3 SSR (withdrawn 2009) 4 Vitamin K antagonist: Tecarfarin (Ph II completed) 2 Tissue factor/VIIa

19 19 Thrombin is the central player in the coagulation cascade Thrombin has several properties that make it an excellent target for anticoagulation 1 Thrombin: –Converts soluble fibrinogen to fibrin – the essential step in thrombus (clot) formation –Activates factor XIII to favour the formation of cross-linked bonds among fibrin molecules –Triggers additional thrombin generation by activating factors V and VIII –Stimulates thrombus-activated fibrinolysis inhibitor (TAFI) resulting in inhibition of fibrinolysis –Is the single most potent stimulus for platelet activation 1. Di Nisio M et al. N Engl J Med 2005;353:1028–40

20 20 Direct thrombin inhibitors (DTIs) block both circulating and clot-bound thrombin Thrombin generation Clot-bound thrombin Heparin Conversion of fibrinogen to fibrin DTIs: dabigatran etexilate ximelagatran* AZD0837 Amplification Anti- thrombin Adapted from Eikelboom J et al. J Am Coll Cardiol 2003;41:70S–8S DTIs: dabigatran etexilate ximelagatran* AZD0837 *Withdrawn from the market in 2006

21 21 ThrombinII Fibrinogen Fibrin clot Direct and indirect factor Xa (FXa) inhibition Adapted from Turpie AG et al. N Engl J Med 2001;344:619–25 AT Indirect FXa inhibitor AT FXa Direct FXa inhibitor INDIRECT Binds to antithrombin (AT) and potentiates the activity of AT against FXa (e.g. idraparinux, SSR ) DIRECT Binds directly to the active site of FXa, blocking substrate interactions (e.g. apixaban, rivaroxaban, edoxaban, betrixaban)

22 22 Summary: targets of novel antithrombotic agents Thrombin is the central player in the blood-clotting process and has several key properties that make it an excellent target for inhibition Direct thrombin inhibitors (e.g. dabigatran, ximelagatran and AZD0837) act directly on free and clot-bound thrombin, blocking its substrate interactions and thereby preventing fibrin formation Factor Xa (FXa) can be inhibited by antithrombotics either: –Indirectly, through binding to antithrombin (e.g. idraparinux and SSR ) –Directly, by interacting with the active site of FXa and blocking its substrate interactions (e.g. apixaban, rivaroxaban and edoxaban)

23 Direct thrombin inhibitors

24 24 Direct thrombin inhibitors (DTIs): past and present A well-established approach to antithrombotic therapy 1 CharacteristicHirudinBivalirudinArgatroban Ximelagatran* and melagatran Dabigatran etexilate AZD0837 Route of administration IV, SCIV IV, SC, oralOral Half-life60–120 min 25 min45 min2–5 hrs12–17 hrs9–14 hrs ClearanceKidney (100%) 2 Kidney (50%), endogenous peptidases (50%) 3 Liver (65%), kidney (20%) 4 Kidney (70%) 5 Kidney (80%) 6 Kidney, intestine 7 *Withdrawn in 2006 IV = intravenous; SC = subcutaneous 1. Data from Di Nisio M et al. N Engl J Med 2005;353:1028–40; 2. Markwardt F et al. Thromb Haemost 1984;52:160–3; 3. Markwardt F et al. Biomed Biochim Acta 1987;46:237–44; 4. Novastan: SmPC, 2009; 5. Erikkson UG et al. Drug Metab Dispos 2003;31:294–305; 6. Pradaxa: SmPC, 2009; 7. Lip GY et al. Eur Heart J 2009;30:2897–907

25 25 Dabigatran etexilate Oral prodrug, converted to dabigatran, which is a potent and reversible direct thrombin inhibitor (DTI) Inhibits both clot-bound and free thrombin 6.5% bioavailability Peak plasma levels of dabigatran achieved within 2 hours after administration in healthy volunteers Half-life of 12–17 hours ~80% renal excretion Most advanced DTI in Phase III development for stroke prevention in patients with AF –Recently demonstrated superiority to warfarin in the Phase III RE-LY ® study Pradaxa: SmPC, 2009; Connolly SJ et al. N Engl J Med 2009;361:1139–51 Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details.

26 26 Dabigatran etexilate has key features that make it an effective antithrombotic for stroke prevention Twice-daily dosing 1 Predictable and consistent pharmacokinetic profile 2,3 Rapid onset/offset of action 2 No requirement for anticoagulation monitoring 4 Low potential for drug–drug interactions 1,5 Not metabolized by CYP450 enzymes, and does not affect the metabolism of other drugs that utilize this system 1,5 No food–drug interactions, with dosing independent of meals or dietary restrictions 6 1. Pradaxa: SmPC, 2009; 2. Stangier J et al. Clin Pharmacokinet 2008;28:47–59; 3. Stangier J Clin Pharmacokinet 2008;47:285–95; 4. Stangier J et al. Br J Pharmacol 2007;64:292–303; 5. Blech S et al. Drug Metab Dispos 2008;36:386–99; 6. Stangier J et al. J Clin Pharmacol 2005;45:555–63 Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details.

27 27 Phase III RE-LY ® : largest AF outcomes trial patients randomized during 2 years 1,2 50% of enrolled patients are naïve to previous oral anticoagulant Median treatment duration: 2 years 951 centres in 44 countries December 2005 to March 2009 Results first presented at ESC congress 2009 and published online in New England Journal of Medicine on 30 Aug 2009 RE-LY ® : Randomized Evaluation of Long-term anticoagulant therapy 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 ESC = European Society of Cardiology Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details.

28 28 Phase III RE-LY ® : study design Ezekowitz MD et al. Am Heart J 2009;157:805–10; Connolly SJ et al. N Engl J Med 2009;361:1139–51 Primary objective: to establish the non-inferiority of dabigatran to warfarin Minimum 1 year follow-up, maximum of 3 years and median of 2 years of follow-up AF with  1 risk factor Absence of contraindications* R Dabigatran 110 mg BID n=6000 Warfarin 1 mg, 3 mg, 5 mg (INR 2.0–3.0) n=6000 Dabigatran 150 mg BID n=6000 *Severe heart-valve disorder, stroke ≤14 days or severe stroke ≤6 months before screening, increased haemorrhage risk, creatinine clearance <30 mL/min, active liver disease, pregnancy; BID = twice daily; INR = international normalized ratio Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details.

29 Phase III RE-LY ® : study inclusion and exclusion criteria Ezekowitz MD et al. Am Heart J 2009;157:805–10; Connolly SJ et al. N Engl J Med 2009;361:1139–51 Exclusion criteria 1.Severe heart-valve disorder 2.Stroke within 14 days or severe stroke within 6 months before screening 3.Any condition that increases the risk of haemorrhage 4.Creatinine clearance <30 mL per min 5.Active liver disease 6.Pregnancy Inclusion criteria 1.Documented AF 2.One additional risk factor for stroke: History of previous stroke, transient ischaemic attack or systemic embolism LVEF less than 40% Symptomatic heart failure, NYHA Class II or greater Age of 75 yrs or more Age of 65 yrs or more and one of the following additional risk factors: diabetes mellitus, coronary artery disease or hypertension

30 30 Primary efficacy endpoint Secondary efficacy endpoints Safety criteria include All stroke (ischaemic + haemorrhagic) and systemic embolism All stroke (ischaemic + haemorrhagic) Systemic embolism All death All stroke (ischaemic + haemorrhagic) Systemic embolism Pulmonary embolism Acute MI Vascular death (including deaths from bleeding) Net clinical benefit: composite of stroke, systemic embolism, PE, MI, death, major bleeding Primary safety outcome: major bleeding events Intracranial haemorrhage Cerebral haemorrhage Subdural haematoma Subarachnoid haemorrhage Elevations in liver enzymes or hepatic dysfunction Phase III RE-LY ® : outcome measures Connolly SJ et al. N Engl J Med 2009;361:1139–51 MI = myocardial infarction; PE = pulmonary embolism Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details.

31 31 Phase III RE-LY ® : baseline characteristics Connolly SJ et al. N Engl J Med 2009;361:1139–51 Characteristic Dabigatran 110 mg BID Dabigatran 150 mg BID Warfarin Randomized (n) Mean age (yrs) Male (%) CHADS 2 score (mean) /1(%) (%) (%) Prior stroke/TIA (%) Prior MI (%) CHF (%) Baseline ASA (%) Warfarin-naïve (%) ASA = acetylsalicylic acid (aspirin); BID = twice daily; CHF = congestive heart failure; MI = myocardial infarction; TIA = transient ischaemic attack Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details.

32 32 Connolly SJ et al. N Engl J Med 2010;363:1875–6 Error bars = 95% CI; BID = twice daily Phase III RE-LY ® : risk of stroke or systemic embolism Dabigatran 110 mg BID vs. warfarin Dabigatran 150 mg BID vs. warfarin <0.001 Superiority P-value 0.30 <0.001 Non-inferiority P-value Hazard ratio Margin = 1.46 Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details.

33 33 Phase III RE-LY ® : time to first stroke or systemic embolism BID = twice daily; NI = non-inferiority; RR = relative risk; RRR = relative risk reduction; Sup = superiority Years Cumulative hazard rates 0.00 Warfarin Dabigatran 110 mg BID Dabigatran 150 mg BID RR 0.90 (95% CI: 0.74–1.10) P<0.001 (NI) P=0.30 (Sup) RR 0.65 (95% CI: 0.52–0.81) P<0.001 (NI) P<0.001 (Sup) RRR 35% Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details. Connolly SJ et al. N Engl J Med 2010;363:1875–6

34 34 Phase III RE-LY ® : haemorrhagic stroke Connolly SJ et al. N Engl J Med 2009;361:1139–51; Connolly SJ et al. N Engl J Med 2010;363:1875–6 BID = twice daily; RR = relative risk; RRR = relative risk reduction; Sup = superiority Haemorrhagic stroke (no. of events) n: Dabigatran 110 mg BID Dabigatran 150 mg BID Warfarin % % % RR 0.31 (95% CI: 0.17–0.56) P<0.001 (Sup) RR 0.26 (95% CI: 0.14–0.49) P<0.001 (Sup) RRR 69% RRR 74% Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details.

35 35 Phase III RE-LY ® : major bleeding BID = twice daily; RR = relative risk; RRR = relative risk reduction; Sup = superiority Major bleeding (%/yr) Dabigatran 110 mg BID Dabigatran 150 mg BID Warfarin Events/n:342/ / /6022 RR 0.80 (95% CI: 0.70–0.93) P=0.003 (Sup) RR 0.93 (95% CI: 0.81–1.07) P=0.32 (Sup) RRR 20% Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details. Connolly SJ et al. N Engl J Med 2010;363:1875–6

36 36 Phase III RE-LY ® : intracranial bleeding BID = twice daily; RR = relative risk; RRR = relative risk reduction; Sup = superiority Events/n:27/601538/607690/6022 Dabigatran 110 mg BID Dabigatran 150 mg BID Warfarin Intracranial bleeding (%/yr) RR 0.30 (95% CI: 0.19–0.45) P<0.001 (Sup) RR 0.41 (95% CI: 0.28–0.60) P<0.001 (Sup) RRR 70% RRR 59% Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details. Connolly SJ et al. N Engl J Med 2010;363:1875–6

37 37 Phase III RE-LY ® : cumulative risk of ALT or AST >3xULN after randomization Connolly SJ et al. N Engl J Med 2009;361:1139–51 ALT = alanine transaminase; AST = aspartate transaminase; BID = twice daily; ULN = upper limit of normal Years Cumulative hazard rates 0.00 Warfarin Dabigatran 110 mg BID Dabigatran 150 mg BID Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details.

38 38 Phase III RE-LY ® : conclusions Dabigatran etexilate has been shown to concurrently reduce both thrombotic and haemorrhagic events Both doses of dabigatran provide different and complementary advantages over warfarin –150 mg BID has superior efficacy with similar bleeding –110 mg BID has significantly less bleedings with similar efficacy Connolly SJ et al. N Engl J Med 2009;361:1139–51; BID = twice daily; INR = international normalized ratio Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details.

39 39 Ximelagatran: proof-of-concept for direct thrombin inhibition First oral direct thrombin inhibitor (DTI) to launch in Europe for stroke prevention in AF At least as effective as dose-adjusted warfarin for the prevention of stroke in high-risk patients with AF 1,2 Associated with lower bleeding rates than warfarin Wider therapeutic index than warfarin Fixed dosing without the need for anticoagulation monitoring BUT, associated with serious liver toxicity in a significant proportion of patients –Approximately 1 in 200 patients treated with long-term ximelagatran had severe liver injury 3 1. Olsson SB et al. Lancet 2003;362:1691–8; 2. Albers GW et al. JAMA 2005;293:690–8; 3. Integrated Executive Summary of FDA Review for NDA Exanta (Ximelagatran), 2004; available at Backgrounder-Execsummaryredacted.pdf; accessed Feb 2010  Withdrawn from clinical development and all markets in 2006

40 40 Study design of SPORTIF III and V trials Stroke Prevention using an ORal direct Thrombin Inhibitor in atrial Fibrillation Patients with non-valvular AF and risk factors for stroke N=7329 Adjusted-dose warfarin (target INR 2.0–3.0) Fixed-dose ximelagatran (36 mg BID) SPORTIF III: 1 23 nations Open-label (n=3407) SPORTIF V: 2 US, Canada Double-blind (n=3922) 1. Olsson SB et al. Lancet 2003;362:1691–8; 2. Albers GW et al. JAMA 2005;293:690–8 BID = twice daily; INR = international normalized ratio

41 41 SPORTIF trials: study inclusion and exclusion criteria Inclusion criteria 1.Age  18 yrs 2.Persistent/paroxysmal AF plus  1 of the following: Hypertension Age  75 yrs Previous stroke, transient ischaemic attack or systemic embolism LVEF <40% or congestive heart failure Age  65 yrs with coronary artery disease or diabetes LVEF = left ventricular ejection fraction; ULN = upper limit of normal Exclusion criteria 1.Mitral stenosis or prior heart valve surgery 2.Major surgery or trauma within 30 days 3.Recent gastrointestinal bleeding 4.Percutaneous coronary intervention within 30 days 5.Endocarditis 6.Active liver disease or elevated liver enzymes  2xULN 7.Renal insufficiency with a calculated creatinine clearance <30 mL/min Akins PT et al. Stroke 2007;38:874–80

42 Difference in absolute event rates (ximelagatran – warfarin) –4 SPORTIF III 1 SPORTIF V 2 Pooled 3 4–302 Ximelagatran better Warfarin better –2–113 Stroke and systemic embolism 42 Non-inferiority of ximelagatran compared with warfarin in patients with AF 1. Olsson SB et al. Lancet 2003;362:1691–8; 2. Albers GW et al. JAMA 2005;293:690–8; 3. Albers GW. Am J Manag Care 2004;10(14 Suppl):S462–9; discussion S469–73 Non-inferiority – –0.03 P=0.10 P=0.13 P=0.94

43 43 Ximelagatran was associated with a trend for fewer major bleeding events in patients with AF 1. Olsson SB et al. Lancet 2003;362:1691–8; 2. Albers GW et al. JAMA 2005;293:690–8; 3. Albers GW. Am J Manag Care 2004;10(14 Suppl):S462–9; discussion S469–73 1.8% 1.3% 3.1% 2.4% 2.5% 1.9% P=0.054 P=0.150 P=0.228 WarfarinXimelagatran Major bleeding events (% patients/yr) 4 SPORTIF III 1 SPORTIF V 2 Pooled

44 44 Ximelagatran has greater net clinical benefit compared with warfarin in patients with AF 6.1% 4.6% 6.3% 5.8% 6.2% 5.2% RRR 26% P=0.019 RRR 7% P=0.527 RRR 16% P= SPORTIF III 1 SPORTIF V 2,3 Pooled Primary events* + major bleeding + death (% patients/yr) Net clinical benefit: composite outcome of stroke, systemic embolic events, major bleeding and all-cause mortality; RRR = relative risk reduction 1. Olsson SB et al. Lancet 2003;362:1691–8; 2. Albers GW et al. JAMA 2005;293:690–8; 3. Lip GY et al. EHJ Suppl 2005;7:E21–5; 4. Albers GW. Am J Manag Care 2004; 10(14 Suppl):S462–9; discussion S469–73 WarfarinXimelagatran

45 45 Time-dependent elevation of liver enzymes (ALT >3xULN): pooled analysis of SPORTIF III and V trials Albers GW. Am J Manag Care 2004;10(14 Suppl):S462–9; discussion S469–73 0.8% ALT >3xULN Event rate (%) % Month Incidence of ALT >3xULN (n) ALT = alanine transaminase; ULN = upper limit of normal WarfarinXimelagatran Figures reproduced with permission: ©2004, Managed Care & Healthcare Communications, LLC

46 46 AZD0837 Prodrug converted to the selective and reversible direct thrombin inhibitor, AR-H Half-life of AR-H is 9–14 hours in healthy subjects Excreted in the urine and faeces Phase II, randomized, double-blind, dose-guiding study completed in patients with AF to assess safety, tolerability, pharmacokinetics and pharmacodynamics –AF patients (n=955) with  1 additional risk factors for stroke were randomized to receive AZD0837 (150, 300 or 450 mg OD or 200 mg BID) or a VKA for 3–9 months –~30% of patients were naïve to VKA treatment Lip GY et al. Eur Heart J 2009;30:2897  907 BID = twice daily; OD = once daily; VKA = vitamin K antagonist

47 47 Lower doses of AZD0837 are associated with less bleeding than VKA VKAAZD0837 BID = twice daily; INR = international normalized ratio; OD = once daily; VKA = vitamin K antagonist Lip GY et al. Eur Heart J 2009;30:2897– % 14.5% 11.0% 5.3% 14.1% Any bleeding (% patients) mg OD 300 mg OD 450 mg OD 200 mg BID INR 2.0–3.0

48 48 Preliminary clinical results with AZD0837 AZD0837 was generally well tolerated at all doses Most commonly reported adverse events were gastrointestinal disorders (e.g. diarrhoea, flatulence or nausea) While the study was not powered to compare stroke and systemic embolic events associated with AZD0837 and VKAs, few events were reported in either treatment arm: –Ischaemic stroke (two on AZD mg OD, one on VKA) –Transient ischaemic attack (one on AZD mg BID, one on VKA) –Systemic embolus (one on AZD mg OD) Frequency of serum ALT >3xULN was similar for AZD0837 and VKA treatment  AZD mg OD provides similar suppression of thrombogenesis (based on levels of D-dimer) to dose-adjusted VKA, with a lower risk of bleeding Lip GY et al. Eur Heart J 2009;30:2897–907 BID = twice daily; OD = once daily; ULN = upper limit of normal; VKA = vitamin K antagonist

49 49 Summary: direct thrombin inhibitors (DTIs) Proof-of-concept for direct thrombin inhibition has been provided with ximelagatran –Withdrawn from clinical development and all markets in 2006 due to liver toxicity Landmark studies have shown clinical effectiveness for DTIs in large Phase III trials The pivotal Phase III trial (RE-LY ® ) recently demonstrated superiority of dabigatran to warfarin in the prevention of stroke in patients with AF Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details.

50 Direct factor Xa inhibitors

51 51 Ongoing Phase III trials with direct factor Xa inhibitors for the prevention of stroke in patients with AF Trial acronym DrugDoseComparatorN CHADS 2 score Expected completion date ARISTOTLE 1,2 Apixaban 5 mg BID Warfarin (INR 2.0–3.0) ≥1Apr 2011 AVERROES 3,4 Apixaban 5 mg BID Aspirin (81–324 mg OD) 6000≥1Aug 2010 ROCKET-AF 5,6 Rivaroxaban 20 mg* OD Warfarin (INR 2.0–3.0) ≥2May 2010 ENGAGE-AF TIMI 48 7 Edoxaban 30 mg OD 60 mg OD Warfarin (INR 2.0–3.0) ≥2Mar 2011 *Adjusted based on renal function; BID = twice daily; INR = international normalized ratio; OD = once daily 1. NCT at accessed Sept 09; 2. Lopes RD et al. Am Heart J 2010;159:331–9; 3. NCT at accessed Sept 09; 4. Eikelboom JW et al. Am Heart J 2010;159:348–53; 5. NCT at accessed Sept 09; 6. ROCKET-AF Study Investigators. Am Heart J 2010;159:340–477; 7. NCT ; available at accessed Sept 09

52 52 Apixaban Highly selective and potent inhibitor of factor Xa Bioavailability of >50% Half-life of between 9 and 14 hours Metabolized in the liver via CYP3A4 –Eliminated through renal (~25%) and intestinal routes (~70%) Two Phase III studies are currently underway to investigate stroke prevention in AF –ARISTOTLE (vs. warfarin) –AVERROES (vs. Aspirin) Khoo CW et al. Int J Clin Pract 2009;63:630–41

53 53 Apixaban and stroke prevention in AF: Phase III ARISTOTLE Randomized, double-blind, non-inferiority trial 1 Investigating the safety and efficacy of apixaban 5 mg BID compared with dose-adjusted warfarin Approximately patients with non-valvular AF Primary outcome: –Stroke or systemic embolism Secondary outcomes: –Ischaemic stroke, haemorrhagic stroke, systemic embolism and all causes of death 1. Lopes RD et al. Am Heart J 2010;159:331–9

54 54 Phase III ARISTOTLE: study inclusion criteria LVEF = left ventricular ejection fraction Inclusion criteria 1.Males and females aged  18 yrs with documented AF 2.Presence of at least one of the following risk factors for stroke (CHADS 2  1):  Age  75 yrs  Previous stroke, transient ischaemic attack or systemic embolism  Symptomatic congestive heart failure or left ventricular dysfunction with LVEF  40%  Diabetes mellitus or hypertension requiring pharmacological treatment Lopes RD et al. Am Heart J 2010;159:331–9

55 55 Phase III ARISTOTLE: study exclusion criteria Exclusion criteria 1.AF or flutter due to reversible causes (e.g. thyrotoxicosis, pericarditis) 2.Clinically significant (moderate or severe) mitral stenosis 3.Increased bleeding risk 4.Conditions other than AF that require chronic anticoagulation 5.Persistent, uncontrolled hypertension 6.Active infective endocarditis 7.Planned major surgery (e.g. AF or flutter ablation procedure) 8.Use of an unapproved, investigational drug or device within the past 30 days 9.Required treatment with Aspirin >165 mg/day 10.Simultaneous treatment with both Aspirin and a thienopyridine (e.g. clopidogrel, ticlopidine) 11.Severe comorbid condition with life expectancy of <1 yr 12.Active alcohol or drug abuse 13.Recent stroke (within 7 days) 14.Severe renal insufficiency 15.Platelet count < /mm 3 16.Haemoglobin <9 g/dL 17.Inability to comply with INR monitoring INR = international normalized ratio Lopes RD et al. Am Heart J 2010;159:331–9

56 56 Apixaban and stroke prevention in AF: Phase III AVERROES Randomized, double-blind, superiority trial 1 Investigating the safety and efficacy of apixaban 5 mg BID compared with Aspirin (81–324 mg OD) Approximately 6000 patients with AF at high-risk of developing stroke who are either unsuitable for or have failed prior warfarin treatment Primary objective: –Determine whether apixaban is superior to Aspirin for preventing the composite outcome of stroke or systemic embolism Secondary objective: –Determine whether apixaban is superior to Aspirin for preventing the composite outcome of stroke, systemic embolism, myocardial infarction or vascular death (major vascular events) Study halted following a predefined interim analysis by an independent data monitoring committee, which revealed “clear evidence of a clinically important reduction in stroke and systemic embolism” 1. Eikelboom JW et al. Am Heart J 2010;159:348–53 BID = twice daily; OD = once daily

57 57 Phase III AVERROES: study design Connolly SJ et al. Presented at ESC 2010; session number Available at: AVERROES.aspx [Accessed September 2010] Primary objective: to establish the superiority of apixaban over Aspirin 36 countries, 522 centres, double-blind study AF with  1 risk factor and demonstrated or expected unsuitable for VKA R Apixaban 5 mg BID (2.5 mg BID in selected patients) Aspirin 81–324 mg/d VKA = vitamin K antagonist; BID = twice daily

58 58 Phase III AVERROES: study inclusion criteria Inclusion criteria 1.Minimal eligible age for the study is 50 yrs 2.Permanent, persistent or paroxysmal AF documented by 12-lead ECG on the day of screening 3.Presence of at least one of the following risk factors for stroke (CHADS 2  1): Prior stroke or transient ischaemic attack Age  75 yrs Arterial hypertension on treatment Diabetes mellitus Heart failure: NYHA Class II or greater at time of enrolment LVEF  35% documented within 6 months of enrolment Documented peripheral arterial disease (previous arterial revascularization, limb or foot amputation, or current intermittent claudication with ankle–arm systolic blood pressure ratio <0.9) ECG = electrocardiogram; LVEF = left ventricular ejection fraction; NYHA = New York Health Association Eikelboom JW et al. Am Heart J 2010;159:348–53

59 59 Phase III AVERROES: study exclusion criteria Exclusion criteria 1.AF due to reversible causes (e.g. thyrotoxicosis, pericarditis) 2.Valvular disease requiring surgery 3.Planned AF ablation procedure within 3 months 4.Conditions other than AF that require chronic anticoagulation 5.Patients with serious bleeding in the past 6 months or at high risk of bleeding: Active peptic ulcer disease Platelet count < /mm 3 or haemoglobin <10 g/dL Recent stroke (within 10 days) Documented haemorrhagic tendencies or blood dyscrasias 6.Current alcohol or drug abuse, or psychosocial reasons that make study participation impractical 7.Severe comorbid condition with life expectancy <1 yr 8.Severe renal insufficiency Serum creatinine >2.5 mg/dL or a calculated creatinine clearance <25 mL/min 9.ALT or AST >2xULN or a total bilirubin 1.5xULN (unless an alternative causative factor [e.g. Gilbert's syndrome] is identified) 10.Women who are pregnant or breastfeeding ALT = alanine transferase; AST = aspartate transferase; ULN = upper limit of normal Eikelboom JW et al. Am Heart J 2010;159:348–53

60 60 Phase III AVERROES: baseline characteristics CharacteristicApixabanAspirin Randomized Age (mean±SD)70±10 yrs Male59%58% CHADS 2 score (mean±SD)2.1±1.1 0–136%37% 2 34% 3+27%29% Prior stroke/TIA14%13% Diabetes19%20% Hypertension86%87% CHF40%38% Baseline ASA76%74% Unsuitable for VKA VKA used and discontinued39%40% VKA expected unsuitable61%60% TIA = transient ischaemic attack; CHF = congestive heart failure; VKA = vitamin K antagonist Connolly SJ et al. Presented at ESC 2010; session number Available at: reports/Pages/708-3-AVERROES.aspx [Accessed September 2010]

61 61 Phase III AVERROES: stroke or systemic embolic event Connolly SJ et al. Presented at ESC 2010; session number Available at: reports/Pages/708-3-AVERROES.aspx [Accessed September 2010] RR = relative risk; CI = confidence interval Cumulative risk Months Aspirin Apixaban RR % CI: 0.33–0.64 P<0.001 Aspirin Apixaban

62 62 Phase III AVERROES: secondary efficacy outcomes Outcome ApixabanAspirinApixaban vs. Aspirin Events Annual rate Events Annual rate RR95% CIP value Stroke, SEE, MI or vascular death –0.83<0.001 MI – Vascular death – Cardiovascular hospitalization –0.91<0.001 Total death – RR = relative risk; CI = confidence interval; SEE = systemic embolic event; MI = myocardial infarction Connolly SJ et al. Presented at ESC 2010; session number Available at: reports/Pages/708-3-AVERROES.aspx [Accessed September 2010]

63 63 Phase III AVERROES: major bleeding RR = relative risk; CI = confidence interval Aspirin Apixaban Cumulative risk Months No. at risk RR % CI: 0.74–1.75 P=0.56 Aspirin Apixaban Connolly SJ et al. Presented at ESC 2010; session number Available at: reports/Pages/708-3-AVERROES.aspx [Accessed September 2010]

64 64 Phase III AVERROES: bleeding Outcome ApixabanAspirinApixaban vs. Aspirin Events Annual rate Events Annual rate RR95% CIP value Major – Clinically relevant, non-major – Minor – Fatal – Intracranial – RR = relative risk; CI = confidence interval Connolly SJ et al. Presented at ESC 2010; session number Available at: reports/Pages/708-3-AVERROES.aspx [Accessed September 2010]

65 65 Phase III AVERROES: permanent discontinuation of study medication RR = relative risk; CI = confidence interval Connolly SJ et al. Presented at ESC 2010; session number Available at: reports/Pages/708-3-AVERROES.aspx [Accessed September 2010] Aspirin Apixaban 0 Months No. at risk Cumulative risk RR % CI: 0.78–1.00 P=0.04 Aspirin Apixaban

66 66 Phase III AVERROES: conclusions Apixaban, in patients with atrial fibrillation who are at risk of stroke and are unsuitable for VKA therapy: –Reduces the risk of stroke or systemic embolism by 54% over an antiplatelet with no significant increase in risk of major haemorrhage –Offers an important advantage over Aspirin for prevention of stroke –Data comparing apixaban with warfarin are expected in 2011 (ARISTOTLE trial) VKA = vitamin K antagonist Connolly SJ et al. Presented at ESC 2010; session number Available at: reports/Pages/708-3-AVERROES.aspx [Accessed September 2010]

67 67 Rivaroxaban Highly selective and potent inhibitor of factor Xa Bioavailability of 60–80% 1 Half-life of up to 9 hours in healthy young subjects and 11–13 hours in the elderly 2 Approved in Europe and Canada for the prevention of venous blood clots in patients undergoing elective hip- or knee- replacement surgery 3 Compound has no direct effect on platelet aggregation 4 Well-tolerated in healthy human subjects 5,6 Rapid onset of action 5,6 Dose-proportional pharmacokinetics/pharmacodynamics 5,6 1. Khoo CW et al. Int J Clin Pract 2009;63:630–41; 2. FDA Advisory Committee Briefing Document: Rivaroxaban, 2009; available at Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/ucm htm, accessed Feb 2010; 3. Xarelto: SmPC, 2009; 4. Perzborn E et al. J Thromb Haemost 2005;3:514–21; 5. Kubitza D et al. Clin Pharmacol Ther 2005;78:412–21; 6. Kubitza D et al. Eur J Clin Pharmacol 2005;61:873–80

68 68 Rivaroxaban has clinical potential for drug–drug interactions with the CYP450 system Metabolized by CYP450 enzymes in the liver Approximately two-thirds of administered rivaroxaban is metabolically degraded by CYP3A4, CYP2J2 and CYP-independent mechanisms 1 Not recommended as concomitant treatment with CYP3A4 inhibitors: 1 –Azole antimycotics (e.g. ketoconazole, itraconzole, voriconazole and posaconazole) –HIV protease inhibitors (e.g. ritonavir) Co-administration with strong CYP3A4 inducers should be performed with caution: 1 –Rifampicin, phenytoin, carbmazepine, phenobarbital, St John’s wort 1. Xarelto: SmPC, 2009 HIV = human immunodeficiency virus

69 69 Rivaroxaban and stroke prevention in AF: Phase III ROCKET-AF Randomized, double-blind, non-inferiority study Approximately patients with AF Comparing the efficacy and safety of rivaroxaban 20 mg OD with warfarin for the prevention of stroke –Patients with moderate renal impairment (creatinine clearance 30–49 mL/min) will receive a fixed dose of 15 mg OD rivaroxaban Primary outcomes: –Any stroke or non-CNS systemic embolism –Composite of major and clinically relevant non-major bleeding events Secondary outcomes: –Each category of bleeding events and adverse events –Composite of stroke, non-CNS systemic embolism and vascular death ROCKET-AF Study Investigators. Am Heart J 2010;159:340–477 CNS = central nervous system; OD = once daily

70 70 Phase III ROCKET-AF: study inclusion criteria Inclusion criteria 1.Male and female patients aged  18 yrs 2.Persistent or paroxysmal AF on  2 episodes (one of which is documented by ECG within 30 days of enrollment) 3.History of stroke, transient ischaemic attack or systemic embolism, or at least two of the following risk factors (CHADS2  2): Congestive heart failure or LVEF  35% Hypertension Age  75 yrs Diabetes mellitus ECG = electrocardiogram; LVEF = left ventricular ejection fraction ROCKET-AF Study Investigators. Am Heart J 2010;159:340–477

71 71 Phase III ROCKET-AF: study exclusion criteria VTE = venous thromboembolism Exclusion criteria 1.Cardiovascular-related conditions: Prosthetic heart valve Planned cardioversion AF secondary to reversible causes (i.e. thyrotoxicosis) Active endocarditis Haemodynamically significant mitral stenosis 2.Haemorrhage risk-related factors: Active internal bleeding History of, or condition associated with, increased risk of bleeding, including intracranial bleeding, major surgical procedure or trauma within 30 days, and clinically relevant gastrointestinal bleeding within 6 months 3.Concomitant conditions and therapies Recent stroke (14 days) or transient ischaemic attack (3 days) Indication for anticoagulant therapy for a condition other than AF (e.g. VTE) Pregnancy or breastfeeding Treatment with other therapies include Aspirin (>100 mg daily), intravenous antiplatelets (5 days before randomization), fibrinolytics (10 days before randomization) ROCKET-AF Study Investigators. Am Heart J 2010;159:340–477

72 72 Edoxaban Highly selective and potent inhibitor of factor Xa Phase II dose-ranging study in patients with non-valvular AF completed 1,2 –The safety and tolerability of 30 and 60 mg OD edoxaban were similar to warfarin Phase III ENGAGE-AF TIMI-48 trial to assess safety and efficacy of edoxaban compared with warfarin for stroke prevention in patients with AF is currently underway 3 1. Weitz JI et al. ASH 2008; abstr 33; 2. Giugliano R et al. ISTH 2009; abstr OC-WE-003; 3. NCT ; available at accessed Sept 09 OD = once daily

73 73 Edoxaban and stroke prevention in AF: Phase III ENGAGE-AF TIMI-48 Randomized, double-blind study 1 Approximately patients with AF Comparing the efficacy and safety of edoxaban 30 mg and 60 mg OD with warfarin for the prevention of stroke Primary outcome: –Composite of stroke and systemic embolic events Secondary outcomes: –Composite of stroke, systemic embolic events and all-cause mortality –Major bleeding events 1. NCT ; available at accessed Sept 09 OD = once daily

74 74 Phase III ENGAGE-AF TIMI-48: study inclusion and exclusion criteria Inclusion criteria 1.Male and female patients aged  21 yrs 2.Able to provide written informed consent 3.History of documented AF within the prior 12 months 4.A moderate to high risk of stroke, as defined by CHADS 2 index score of  2 Exclusion criteria 1.Transient AF secondary to other reversible disorders 2.Patients with moderate or severe mitral stenosis, unresected atrial myxoma or a mechanical heart valve 3.Patients with any contraindication for anticoagulant agents 4.Patients with conditions associated with high risk of bleeding or with known or suspected hereditary or acquired bleeding disorders 5.Females of childbearing potential, including: History of tubal ligation <2 yrs postmenopausal NCT ; available at accessed Sept 09

75 75 Summary: direct factor Xa inhibitors Apixaban, rivaroxaban and edoxaban are highly selective and potent inhibitors of factor Xa Several Phase III studies are comparing the efficacy and safety of direct factor Xa inhibitors with warfarin for stroke prevention in AF: –ARISTOTLE (apixaban) –ROCKET-AF (rivaroxaban) –ENGAGE-AF TIMI-48 (edoxaban) For patients with AF who are unsuitable or have failed warfarin therapy, the efficacy and safety of direct factor Xa inhibitors have been compared with those of Aspirin –AVERROES has reported that apixaban significantly reduces the risk of stroke or systemic embolism over Aspirin with no significant increase in risk of major haemorrhage 1 1. Connolly SJ et al. Presented at ESC 2010; session number Available at: reports/Pages/708-3-AVERROES.aspx [Accessed September 2010]

76 Indirect factor Xa inhibitors

77 77 Idraparinux Bioavailability approaching 100% after subcutaneous administration 1 Binds antithrombin with such high affinity that it has a similar half-life to antithrombin (80 hours) 2 Given once-weekly and does not require anticoagulation monitoring 2 Not metabolized; excreted unchanged via the kidneys 2 –Dose must be reduced in patients with renal insufficiency –Contraindicated in patients with creatinine clearance <30 mL/min Phase III VAN GOGH trial assessed the safety and efficacy of idraparinux 2.5 mg once weekly in patients with DVT or PE 3 –Similar efficacy to standard therapy for DVT –Failed to demonstrate non-inferiority for PE Phase III AMADEUS trial to assess safety and efficacy of idraparinux compared with warfarin for stroke prevention in patients with AF terminated due to excess bleeding 4 1. Veyrat-Follet C et al. J Thromb Haemost 2009;7:559–65; 2. Gross PL & Weitz JI. Arterioscler Thromb Vasc Biol 2008;28:380–6; 3. Buller HR et al. N Engl J Med 2007;357:1094–104; 4. Bousser MG et al. Lancet 2008;371:315–21 DVT = deep vein thrombosis; PE = pulmonary embolism

78 78 Idraparinux is associated with clinically relevant bleeding Phase III AMADEUS 1 –Randomized, open-label, non-inferiority study Compared safety and efficacy of idraparinux 2.5 mg once weekly with dose-adjusted warfarin for the prevention of stroke in patients with AF Primary efficacy outcome: –Cumulative incidence of all stroke and systemic embolism Primary safety outcome: –Clinically relevant bleeding Trial stopped after randomization of 4576 patients (2283 idraparinux; 2293 warfarin) and a mean follow-up of 10.7 months –Due to excess clinically relevant bleeding with idraparinux 1. Bousser MG et al. Lancet 2008;371:315–21

79 79 Safety and efficacy of idraparinux for stroke prevention in AF: Phase III AMADEUS Idraparinux (n=2283)Warfarin (n=2293) 0.9% 1.3% P=0.007 (for non-inferiority) 19.7% 11.3% P< Bousser MG et al. Lancet 2008;371:315–21 Incidence (%) 1.5 Stroke and embolism Incidence (%) 20 Clinically relevant bleeding

80 80 Biotinylated version of idraparinux: SSR No antidote for idraparinux to reverse its anticoagulant activity SSR developed to offer the same pharmacological features as idraparinux Addition of biotin allows the rapid removal of the drug following intravenous injection of avidin 1 The bioequipotency of SSR compared with an equimolar dose of idraparinux has been evaluated for the treatment of deep vein thrombosis 2 The Phase III BOREALIS-AF study compared SSR with warfarin for the prevention of stroke in AF 3 SSR was withdrawn from development for stroke prevention in AF in December 2009 as it did not appear to significantly improve the care of patients 4 1. Gross PL & Weitz JI. Arterioscler Thromb Vasc Biol 2008;28:380–6; 2. NCT ; available at accessed Sept 09; 3. NCT ; available at accessed Sept 09; 4. Sanofi-aventis press release Dec 2009; available at aventis.com/binaries/ _rdupdate_en_tcm pdf; accessed Feb 10

81 81 Summary: indirect factor Xa inhibitors Idraparinux has a long half-life of 80 hours that subsequently enables weekly dosing The Phase III AMADEUS study was terminated due to excess bleeding SSR , the biotinylated version of idraparinux, was withdrawn from development for stroke prevention in AF in December 2009

82 82 Conclusions Current anticoagulants have numerous limitations –There is a clear and meaningful unmet clinical need for stroke prevention in patients with AF A number of novel antithrombotic agents have been developed –Factor Xa inhibitors: Direct: apixaban, rivaroxaban and edoxaban (in Phase III development) Indirect: idraparinux and SSR (Phase III trials terminated) –Direct thrombin inhibitors Ximelagatran: provided proof-of-concept but withdrawn from the market in 2006 due to liver toxicity AZD0837: Phase II completed Dabigatran: most advanced in clinical development with recent Phase III data (RE-LY ® ) demonstrating superiority to warfarin Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details.


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