Anti coagulation Treatment Effects of Age Impact of NOAC. June 2014 Dov Gavish MD FESC Tel Aviv University ISRAEL

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1 Anti coagulation Treatment Effects of Age Impact of NOAC June 2014 Dov Gavish MD FESC Tel Aviv University ISRAEL PE

2 VTE: deep vein thrombosis and pulmonary embolism are common in elderly Thrombosis is the formation or presence of a thrombus that may obstruct blood flow through a vein or artery 1 VTE occurs when thrombosis obstructs blood flow through a vein The term VTE encompasses: DVT PE VTE is a serious health issue 2 PE As the venous clot grows, it extends along the vein PE occurs when parts of the clot detach and travel in the blood to block vessels in the lungs Migration Embolus Thrombus DVT, deep vein thrombosis; PE, pulmonary embolism 1. Anderson FA, et al. Center for Outcomes Research, University of Massachusetts Medical Center; Goldhaber SZ. J Am Coll Cardiol 1992;19:

3 VTE rate increase with Age

4 DVT is Common in the elderly The aged have an elevated risk of developing deep vein thrombosis. The annual incidence rate of first DVT in individuals aged years is estimated to be per 1,000, and this doubles in those aged over Older patients also have higher in-hospital mortality associated with pulmonary embolism and DVT, at 21% and 3%, 4 Mar 2013

5 Potential complications and goal of treatment DVT complications: 1,2 PE Damage to valves in the deep veins Venous reflux Post-thrombotic syndrome (PTS) Goal of treatment Prevent embolization to the lungs Prevent extension into larger veins Prevent recurrence Avoid the chronic complications 1. Kearon C. Circulation 2003;107:I22 I30; 2. Ginsberg JS, et al. Arch Intern Med 2000;160:

6 AF is a problem of the older people 6 Mar 2013

7 Risk of stroke in AF. Patterns of recurrent AF may be classified as paroxysmal, persistent, or permanent. Lubitz S A et al. Eur Heart J 2010;31: Published on behalf of the European Society of Cardiology. All rights reserved. The Author For permissions please journals.permissions@oxfordjournals.org

8 Cumulative hazard Stroke risk is evident in sub clinical AF Sub clinical AF* is associated with a 2.5-times greater risk of ischemic stroke or systemic embolism 4.2% vs. 1.7% with no arrhythmia (P=0.007) 0.08 Risk of ischemic stroke or systemic embolism 0.06 Subclinical atrial tachyarrhythmias present Years of follow-up *Sub clinical atrial tachyarrhythmia's detected by implanted devices (n=2580) Healey JS et al. N Engl J Med 2012;366:120 9 Subclinical atrial tachyarrhythmias absent 8 Mar 2013

9 Virchow s triad for thrombogenesis (possibly age related) Atrial fibrillation Left ventricular dysfunction Immobility Venous insufficiency/ varicose veins Atrial fibrillation Trauma/surgery Atherosclerosis Venepuncture Heart valve disease/ replacement Indwelling catheters HYPERCOAGULABLE STATE Atrial fibrillation Malignancy Pregnancy Oestrogen therapy Trauma/surgery Sepsis Thrombophilia Inflammatory bowel disease Nephrotic syndrome Adapted from Watson T et al. Lancet 2009;373: April 2012

10 Prevalence of AF by age group Source: American Journal of Cardiology 2013; 112: (DOI: /j.amjcard ) Copyright 2013 Elsevier Inc. Terms and Conditions

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12 Prevalence of stroke by age and sex (National Health and Nutrition Examination Survey: ). Go A et al. Circulation 2013;127:e6-e245 Copyright American Heart Association

13 Two-year age-adjusted incidence of stroke/1000 AF is a significant risk factor for ischemic stroke No cardiovascular condition Cardiovascular condition * * * * 10 0 High blood pressure Coronary heart disease Congestive heart failure Atrial fibrillation Risk ratio *p<0.001 versus no cardiovascular condition Wolf et al, Stroke 1991

14 Stroke risk in patients with AF (%) Proportion of strokes attributable to AF increases with age Men Women Age (years) Marini et al, Stroke 2005

15 Most strokes associated with AF are ischemic Types of stroke in patients with AF Haemorrhagic (8%) Ischaemic stroke (n=5810) Haemorrhagic stroke (n=484) Ischaemic (92%) Based on data collected in the Danish National Indicator Project for patients hospitalized for stroke (including 6294 patients with AF) Andersen KK et al. Stroke 2009;40: Mar 2013

16 AF annual costs to the EU economy Estimated 6.2 billion* Equates to per patient each year Greece Italy Poland Spain Netherlands Mean annual cost ( /patient) Total country costs ( million) *EuroHeart Study, data Ringborg A et al. Europace 2008;10: Mar 2013

17 Relative risk of stroke Risk of stroke varies widely between patients with AF Depends on a range of factors 1 Annual stroke rates can vary 20-fold with no vs multiple risk factors Prior stroke or TIA History of diabetes History of hypertension History of heart failure Increasing age* Risk factor *Relative risks are based on decades of age TIA = transient ischemic attack 1. Atrial Fibrillation Investigators. Arch Intern Med 1994;154: ; 2. Gage BF et al. JAMA 2001;285: Mar 2013

18 Severe disability (% of stroke patients) The increased disability that results from AF-related stroke persists over time Framingham Heart Study (US) * % 58% AF No AF % 36% 30% % 16% 11% 0 Acute phase 3 months 6 months 12 months Time after stroke event *Severe disability was defined as a score of 40 in the modified Barthel Index for activities of daily living Lin et al, Stroke 1996

19 New slide Risk factors for ischemic stroke Age (years) < Multivariate hazard ratios (95% CI) 1.0 (reference) 2.97 ( ) 5.28 ( ) Female sex 1.17 ( ) Previous ischemic stroke 2.81 ( ) Intracranial bleeding 1.49 ( ) Vascular disease (any) Myocardial infarction Previous CABG Peripheral artery disease 1.14 ( ) 1.09 ( ) 1.19 ( ) 1.22 ( ) Hypertension 1.17 ( ) Heart failure (history) 0.98 ( ) Diabetes mellitus 1.19 ( ) Thyroid disease Thyrotoxicosis 1.00 ( ) 1.03 ( ) CABG = coronary artery bypass graft Camm AJ et al. Eur Heart J doi: /eurheartj/ehs April Mar

20 Estimation of stroke risk in AF Classification scheme Patient population Risk factors identified Atrial Fibrillation Investigators 1 Five randomized studies N=1593, 106 strokes over a mean follow-up 1.4 yrs Age Hypertension Prior cerebral ischemia Diabetes Stroke Prevention and Atrial Fibrillation (SPAF) 2 Two randomized studies N=854, 68 strokes over a mean follow-up 2.3 yrs Blood pressure >160 mmhg Prior cerebral ischemia Recent heart failure Combination of age 75 yrs and female gender Framingham Heart Study 3 Recently identified AF N=705, 83 strokes and 382 strokes or death over a mean follow-up of 4.0 years Age Female gender Diabetes 1. Atrial Fibrillation Investigators. Arch Intern Med 1994;154: ; 2. SPAF Investigators. J Stroke Cerebrovasc Dis 1995;5:147 57; 3. Wang TJ et al. JAMA 2003;290: Mar 2013

21 CHADS 2 score Stroke risk assessment with CHADS CHADS 2 criteria Score Congestive heart failure 1 Hypertension 1 Age 75 yrs 1 Diabetes mellitus 1 Stroke/transient ischaemic attack Annual stroke rate (%)* 30 Gage BF et al. JAMA 2001;285: April Mar

22 Older than 75 =2 points!

23 Updated slide Assessing stroke risk: CHA 2 DS 2 -VASc CHA 2 DS 2 -VASc criteria Score CHF/LV dysfunction 1 Hypertension 1 Age 75 yrs 2 Diabetes mellitus 1 Stroke/TIA/TE 2 Vascular disease 1 Age yrs 1 Total score Patients (n=7329) Adjusted stroke rate (%/year)* Sex category (i.e. female gender) 1 *Theoretical rates without therapy; assuming that warfarin provides a 64% reduction in stroke risk, based on Hart RG et al CHF = congestive heart failure; LV = left ventricular; TE = thromboembolism; TIA = transient ischaemic attack Lip G et al. Chest 2010;137:263 72; Lip G et al. Stroke 2010; 41:2731 8; Camm J et al. Eur Heart J 2010;31: ; Hart RG et al. Ann Intern Med 2007;146: April Mar

24 Updated slide Assessing bleeding risk: HAS-BLED HAS-BLED risk criteria Score Hypertension (SBP >160 mmhg) 1 Abnormal renal or liver function (1 point each) 1 or 2 Stroke 1 Bleeding (history or predisposition) 1 Labile INRs (e.g. <60% TTR) 1 Elderly (e.g. age >65 yrs) 1 Drugs or alcohol (1 point each; includes antiplatelets and NSAIDs) 1 or 2 INR = International normalized ratio; NSAID = non-steroidal anti-inflammatory drug; SBP = systolic blood pressure; TTR = time in therapeutic range ESC guidelines: Camm J et al. Eur Heart J 2010;31: April Mar

25 Risk stratification: Stroke and bleeding

26 26 Mar 2013

27 Treatment options for AF ISCHAEMIC STROKE PREVENTION CONTROL OF HEART RATE MAINTENANCE OF SINUS RHYTHM PHARMACOLOGICAL Dabigatran etexilate Rivaroxaban Vitamin K antagonists (e.g. warfarin) ASA Clopidogrel NON-PHARMACOLOGICAL PHARMACOLOGICAL -blockers Calcium channel blockers (non-dhp) Digoxin NON-PHARMACOLOGICAL PHARMACOLOGICAL Anti-arrhythmic drugs Class IA Class IC Class III NON-PHARMACOLOGICAL Removal/isolation of left atrial appendage Ablation/permanent pacing Ablation Surgery (MAZE procedure) ASA = acetyl salicylic acid; DHP = dihydropyridine Adapted from Prystowsky EN. Am J Cardiol 2000;85:3D 11D Disclaimer: Dabigatran etexilate and rivaroxaban are now approved for clinical use in stroke prevention in atrial fibrillation in certain countries. Please check local prescribing information for further details 27 April Mar

28 Tests to be performed in elderly with AF 28 Mar 2013

29 Geriatric assessment in elderly with AF 29 Mar 2013

30 New slide Challenges and limitations of ASA Limited efficacy for stroke prevention vs VKAs Limited effect on thromboembolic No evidence of reduced mortality with ASA in AF ASA limitations Increased bleeding risk Significant adverse events Unfavourable net clinical benefit ASA = acetylsalicylic acid; VKA = vitamin K antagonist 30 April Mar

31 Limited efficacy of ASA in reducing the risk of stroke in patients with AF Updated slide AFASAK SPAF EAFT ESPS II LASAF 125 mg/d 125 mg QOD UK-TIA 300 mg/d 1200 mg/d JAST All trials ASA better Placebo better Only the SPAF trial showed a benefit of ASA over placebo for reducing stroke risk RRR: 19%* (95% CI: 1 to 35%) RRR (%) 100 *Random effects model; error bars = 95% CI; *P>0.2 for homogeneity; Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic); for ischaemic stroke only, RRR was 21% (95% CI: 1 to 38%) ASA = acetylsalicylic acid; QOD = every other day Hart RG et al. Ann Intern Med 2007;146: April Mar

32 Warfarin reduces the risk of stroke in patients with AF Updated slide Favours warfarin Favours placebo AFASAK SPAF BAATAF CAFA SPINAF EAFT All trials RRR 64%* (95% CI: 49 74%) RRR (%) 100 When only ischaemic stroke was considered, dose-adjusted warfarin was associated with a 67% RRR (95% CI: 54 77%) Random effects model; Error bars = 95% CI; *P>0.2 for homogeneity; Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic), for ischaemic stroke only, the RRR was 67% (95% CI: 54 77%) VKA = vitamin K antagonist Hart RG et al. Ann Intern Med 2007;146: April Mar

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34 Updated slide ASA inferior to warfarin for stroke prevention in AF Warfarin better ASA better AFASAK I AFASAK II Chinese ATAFS EAFT PATAF SPAF II Age 75 yrs Age >75 yrs All trials RRR: 38%* (95% CI: 18 52%) RRR (%) Random effects model; error bars = 95% CI; *P>0.2 for homogeneity; Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic); ASA = acetylsalicylic acid Hart RG et al. Ann Intern Med 2007;146: April Mar

35 Warfarin safer than aspirin at any age 35 Mar 2013

36 New slide Real-world data highlights ASA limitations Registry data highlights increased risk of thromboembolism with ASA vs VKA (n= ) * Compared with VKA, no additional benefit observed with VKA + ASA HR (95% CI) vs VKA for thromboembolism in highthromboembolic-risk patients ASA VKA + ASA No treatment Favours comparator Favours VKA Risk of bleeding increased with VKA, ASA, and VKA + ASA vs no treatment ASA alone was not associated with a positive net clinical benefit *Registry data for all patients with nonvalvular AF in Denmark ASA = acetylsalicylic acid; HR = hazard ratio; VKA = vitamin K antagonist Olesen JB et al. Thromb Haemost 2011;106: April Mar

37 Bleeds/year Bleeds/year Risk of major and intracranial bleeding not significantly different between ASA and OAC New slide Intracranial bleeding Major bleeding OAC (n=48599) ASA (n=61396) HAS-BLED total score* HAS-BLED total score* *Modified HAS-BLED score used in this study: 1 point each for systolic blood pressure <160 mmhg, renal dysfunction, liver dysfunction, stroke, bleeding, age >65 years, drugs affecting bleeding or alcohol abuse (maximum score = 7); score 0 2 indicates low bleeding risk, 3 indicates high bleeding risk; ASA = acetylsalicylic acid; OAC = oral anticoagulant Friberg L et al. Eur Hear J 2012:33: ; Pisters R et al. Chest 2010;138: April Mar

38 Cumulative event rate (% per year) SPAF III: adjusted-dose warfarin compared with low-intensity warfarin plus ASA 15 Ischaemic stroke or systemic embolism 10 Combination therapy Fixed-dose warfarin (INR )* & ASA (325 mg/d) 5 RRR 74% (95% CI: 50 87%) P< Adjusted-dose warfarin Warfarin (INR ) Years n= n= *Warfarin dose adjusted between 0.5 and 3.0 mg/day to achieve international normalized ratio (INR) when initiating therapy and then fixed for rest of study; ASA = acetyl salicylic acid; RRR = relative risk reduction SPAF Investigators. Lancet 1996;348: April Mar

39 Cumulative hazard rates ACTIVE W: dual antiplatelet therapy inferior to oral anticoagulation for stroke prevention in AF 0.05 All stroke RR 1.72 (95% CI: ) P=0.001 Dual antiplatelet therapy Clopidogrel (75 mg/d) & ASA ( mg/d) Oral anticoagulation VKA (target INR = ) Years n= n= For ischaemic stroke: RR 2.17 (95% CI: ) ASA = acetyl salicylic acid; INR = international normalized ratio; RR = relative risk; VKA = vitamin K antagonist ACTIVE Investigators. Lancet 2006;367: April Mar

40 How to start Warfarin in elderly 40 Mar 2013

41 New slide Challenges and limitations of VKAs Slow onset and offset of action Variability in dose response between individuals Subject to multiple food and drug interactions VKAs have many welldocumented limitations Anticoagulation reversal may not improve outcomes Narrow therapeutic window, requiring frequent monitoring ICH = intracranial haemorrhage; VKA = vitamin K antagonist Adapted from Connolly SJ et al. Circulation 2007;116: Risk of haemorrhage (particularly ICH) is high, and outcomes are poor 41 April Mar

42 The risks of ischemic stroke or intracranial bleed are high outside a narrow INR range Odds Ratio Adjusted odds-ratio for ischemic stroke and intracranial bleeding in relation to intensity of anticoagulation Ischaemic stroke risk Intracranial bleeding risk Ischaemic stroke risk Intracranial bleeding risk INR Fuster et al. Circulation 2011;123:e269-e367.Adapted from: Hylek and Singer. Ann Intern Med 1994;120: Oden et al. Thromb Res 2006;117:493-9.

43 Patients (%) Patients stop taking warfarin over time ~30% of AF patients treated with warfarin discontinued within 1 year (from a total population of 41,910 AF patients in the UK General Practice Research Database Patient age Age Age Age Age Age Age Time (years after starting treatment) Adapted from Gallagher et al. J Thromb Haemost 2008;6:1500-6

44 Patients (%) VKA therapy is underused Euro Heart Survey ( ): No VKA therapy in ~40% of AF patients who should be treated None Heparin only Antiplatelet Antiplatelet+VKA VKA (n=332) (n=697) (n=722) (n=371) (n=172) (n=72) (n=15) CHADS 2 score Adapted from Nieuwlaat et al. Eur Heart J 2006;27:

45 Patients unsuitable for VKAs (%) Many patients with AF unsuitable for treatment with VKAs Contraindications most frequent in elderly patients Often at greatest risk of stroke % 30 38% 37% % 0 >65 yrs 1 >65 yrs 2 >75 yrs 3 All ages 4 VKAs = vitamin K antagonists 1. Sudlow M et al. Lancet 1998;352: ; 2. Brass LM et al. Stroke 1997;28:2382 9; 3. Kalra L et al. Stroke 1999;30: ; 4. Go AS et al. Ann Intern Med 1999;131: April Mar

46 Most ischaemic strokes occur in patients who are under-anticoagulated >70% of ischaemic stroke patients with AF had an INR <2.0 Only 10% were within the therapeutic range (INR 2.0) 29% 29% 15% 39% 29% 10% 2% 25% 3% 18% Sub therapeutic warfarin (INR <2.0) Dual antiplatelet therapy No antithrombotics Therapeutic warfarin (INR 2.0) Single antiplatelet therapy Data from a prospective stroke registry of 597 patients with AF INR = international normalized ratio; TIA = transient ischaemic attack Gladstone DJ et al. Stroke 2009;40: April Mar

47 OAC use, CHADS 2 2 (% patients) Global AF registry: use of oral anticoagulants was low and varied between regions 100 Patients with a prior history of AF *P vs North America * 40 * * * * * 20 * 0 North America South America Western Europe Eastern Europe Middle East Africa India China Asia CHADS 2 = Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke, or TIA (2); OAC = oral anticoagulation; TIA = transient ischaemic attack Healey J et al. ESC 2011; e-slides available at (accessed September 2011) 47 April 2012

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49 INR Most strokes in patients on VKAs occur if patients are outside recommended INR ranges Updated slide Target INR range for study ACC/AHA/ESC recommended INR ( ) Stroke event 1.0 AFASAK CAFA SPAF BAATAF SPINAF ACC = American College of Cardiology; AHA = American Heart Association; ESC = European Society of Cardiology; INR = international normalized ratio; VKA = vitamin K antagonist Levi M et al. Semin Thromb Haemost 2009;35: April Mar

50 Strokes can still occur if patients are within recommended INR ranges INR Updated slide Target INR range for study ACC/AHA/ESC recommended INR ( ) Stroke event 1.0 AFASAK CAFA SPAF BAATAF SPINAF ACC = American College of Cardiology; AHA = American Heart Association; ESC = European Society of Cardiology; INR = international normalized ratio Levi M et al. Semin Thromb Haemost 2009;35: April Mar

51 Probability of event by 1 year plus point-wise 95% CI Probability of stroke/non-cns embolism according to cttr Piccini et al., J Am Heart Assoc, 2014 Center TTR (%) calculated from center INR values

52 So what shall we recommend?

53 Summary of the global unmet needs 100 persons with AF ~ One half receive a VKA 1 ~ One half are adequately treated 2 Few are still on treatment at six years 3 Effective, safer and more convenient therapies are urgently needed 1. Nieuwlaat et al. Eur Heart J 2006;27: Healey et al. Presented at the ESC meeting (Sunday August 28, 2011) Gallagher et al. J Thromb Haemost 2008;6: EU API234 Subject to local prior approval by BMS/Pfizer, as per relevant SOP and local rules, slide may be used with external audiences in local BMS/Pfizer arranged meetings

54 Mar

55 Direct thrombin inhibitors (DTIs) block both circulating and clot-bound thrombin Thrombin generation Heparin Antithrombin DTIs: dabigatran etexilate ximelagatran* AZD0837 Conversion of fibrinogen to fibrin Amplification DTIs: dabigatran etexilate ximelagatran* AZD0837 Clot-bound thrombin *Withdrawn from the market in 2006 DTI = direct thrombin inhibitor Adapted from Eikelboom J et al. J Am Coll Cardiol 2003;41:70S 8S Disclaimer: Dabigatran etexilate is now approved for clinical use in stroke prevention in atrial fibrillation in certain countries. Please check local prescribing information for further details 55 April Mar

56 Direct and indirect FXa inhibition INDIRECT Binds to 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) Direct FXa inhibitor AT AT AT FXa FXa Indirect FXa inhibitor II Thrombin AT = antithrombin; FXa = Factor Xa Adapted from Turpie AG et al. N Engl J Med 2001;344: Fibrinogen Fibrin clot Disclaimer: Edoxaban and betrixaban are not approved for clinical use in stroke prevention in atrial fibrillation. Rivaroxaban and Apixaban are approved in this indication in certain countries. Please check local prescribing information for further details 56 April Mar

57 The promise of new oral anticoagulants Simplified dosing regimen No dietary restrictions Predictable anticoagulation and no need for routine coagulation monitoring Can be given at fixed doses Reduced potential for food and drug interactions Less labour-intensive Less impact on patients daily life Improved compliance Reduced administrative costs Improved quality of life Improved efficacy and safety 1. Raghaven N et al. Drugs Metab Dispos 2009;37:74 81; 2. Shantsila E, Lip GY. Curr Opin Investig Drugs 2008;9: ; 3. Mueck W et al. Clin Pharmacokinet 2008;47: ; 4. Mueck W et al. Thromb Haemost 2008;100: ; 5. Mueck W et al. Int J Clin Pharmacol Ther 2007;45:

58 Study design and inclusion ROCKET AF 1 RE-LY 2 ARISTOTLE 3,6 AVERROES 4 ENGAGE AF- TIMI 48 5 No. of patients Statistical objective No. study arms 14,264 18,113 18,201 5,599 20,500 Non-inferiority Noninferiority Noninferiority Superiority Non-inferiority Study drug Control AF type of pts included Double-blind rivaroxaban Double-blind warfarin (INR 2 3) Non-valvular Two doses of double-blind dabigatran Open-label warfarin (INR 2 3) Non-valvular Double-blind Apixaban Double-blind warfarin (INR 2 3) All except mechanical valves Double-blind apixaban Double-blind ASA Non-valvular 1. Patel MR et al, 2011; 2. Connolly SJ et al, 2009; 3. Lopes RD et al, 2010; 4. Connolly SJ et al, 2011; 5. Ruff CT et al, 2010; 6.Granger CB et al, Two doses of double-blind edoxaban Double-blind warfarin (INR 2 3) Non-valvular 58

59 Comparison of the pharmacological characteristics of newer OACs Parameter Dabigatran Rivaroxaban Apixaban Edoxaban Target Thrombin Factor Xa Factor Xa Factor Xa Oral bioavailability 6.5% %* ~66% 50% Plasma protein binding 34 35% 92 95% 87% 40 59% Dosing (for SPAF indication) *After oral ingestion Routine coagulation monitoring Fixed, twice daily Fixed, once daily Fixed, twice daily Fixed, once daily Prodrug Yes No No No Half-life (h) (young healthy) (elderly) T max (h) ~ No No No No Eriksson BI et al, 2011; Frost et al, 2007; Kubitza D et al, 2005; Kubitza D et al, 2005; Ogata K et al, 2010; Stangier et al, 2005; Raghavan N et al, 2009; Xarelto SmPC 2011; Xarelto PI 2011; Pradaxa SmPC 2011; Eliquis SmPC 2011; Dabigatran PI; ROCKET AF Investigators 2010; Lopes et al, 2010; Ruff et al,

60 Comparison of the pharmacological characteristics of new OACs Parameter Dabigatran Rivaroxaban Apixaban Edoxaban Renal clearance 80% 33%; additional 33% cleared after metabolic degradation to inactive drug Potential drug interactions Rifampicin, quinidine, amiodarone, potent P-gp inhibitors Potent inhibitors of both CYP3A4 and P-gp*, strong inducers of CYP3A4 ~25% 35% Potent CYP3A4 inhibitors* Potent inhibitors of both CYP3A4 and P-gp *CYP, cytochrome P-450 isoenzymes; P-gp, P-glycoprotein. Strong inhibitors of both CYP3A4 and Pgp include azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, posaconazole) and protease inhibitors, such as ritonavir. Eriksson BI et al, 2011; Xarelto Summary of Product Characteristics

61 OAC therapy in patients with renal impairment Newer anticoagulants are partially cleared via the renal route 1 However, not all new anticoagulants rely on this route to the same extent 1 Excreted unchanged Rivaroxaban 2 Apixaban 3 Edoxaban 4 Dabigatran etexilate 5 Via kidney ~33%* ~25% # 35% ~80% Potentially managed via dose adjustment *Additional 33% cleared renally after metabolic degradation to inactive drug 6 # Estimated percentage of the orally administered dose Mean percentage after intravenous administration within the first 24 hours of dosing Contraindicated in patients with severe renal impairment 1. Eriksson BI et al, 2011; 2. Weinz C et al, 2009; 3. Raghavan N et al, 2008; 4. Ogata K et al, 2010; 5. Blech S et al, 2008; 6. Xarelto Summary of Product Characteristics

62 Dosing and dose evaluation for special populations ROCKET AF 1 RE-LY 2 ARISTOTLE 3 & AVERROES 4 ENGAGE AF-TIMI 48 5 Rivaroxaban Dabigatran Apixaban Edoxaban 20 mg od (15 mg od) 110 mg bid or 150 mg bid (randomized to two separate arms) 5 mg bid (2.5 mg bid) 30 mg od (15 mg od) or 60 mg od (30 mg od) (randomized to two separate arms) Dose adjustment for patients with: Moderate renal impairment CrCl ml/min No dose adjustment Dose adjustment for patients fulfilling 2 of the following criteria at baseline: Age 80 years Body weight 60 kg Serum creatinine 1.5mg/dl (133 µmol/l) Dose adjustment for patients fulfilling 1 of the following criteria at baseline: Concomitant verapamil or quinidine Body weight 60 kg CrCl ml/min 1. Patel MR et al, 2011; 2. Connolly SJ et al, 2009; 3. Lopes RD et al, 2010; 4. Connolly SJ et al, 2011; 5. Ruff CT et al,

63 Dosing for prevention of stroke in NVAF The recommended dose of apixaban is 5 mg taken orally twice daily (BD), swallowed with water, with or without food. Age 80 years Body weight 60 kg Serum creatinine 1.5 mg/dl (133 µmol/l) Dose Adjustment to 2.5mg BD At least 2 characteristics Severe renal impairment alone (CrCl: ml/min) Apixaban 2.5mg BD Prior to initiating apixaban, liver function testing should be performed If a dose is missed, the patient should take apixaban immediately and then continue with twice daily intake as before Apixaban SmPC EU API234 Subject to local prior approval by BMS/Pfizer, as per relevant SOP and local rules, slide may be used with external audiences in local BMS/Pfizer arranged meetings

64 NOAC Efficacy vs. Warfarin Not head to head comparison For illustrative purposes only ARISTOTLE RELY ROCKET-AF

65 Patient Characteristics Across Trials 30-40% elderly patients * # *CHF or LVEF 40%; #CHF or LVEF 35% Notably higher rates of diabetes, CHF, and prior stroke in ROCKET population Connolly N Engl J Med 2009;361:1139; Patel N Engl J Med :883;Granger N Engl J Med 2011;365:981; Ruff Am Heart J 2010;160:635

66 CHADS 2 Distribution Across Trials % CHADS 2 Score Dabigatran and apixaban: evaluated across a spectrum of stroke risk categories Rivaroxaban: evaluated in patients at high risk of stroke Connolly N Engl J Med 2009;361:1139; Patel N Engl J Med :883; Granger N Engl J Med 2011;365:981; Ruff Am Heart J 2010;160:635

67 Phase III trials vs. warfarin (aim INR ) RELY ROCKET ARISTOTLE Sample size 18,113 14,266 18,201 New treatment Design Dabigatran 110mg BID Dabigatran 150mg BID Non-inferiority PROBE Rivaroxaban 20mg QD Non-inferiority Double-blind TTR- Warfarin Apixaban 5mg BID Non-inferiority Double-blind Patients AF + CHADS2 1 AF + CHADS2 2 AF + CHADS2 1 Primary outcome Stroke (ischemic or hemorrhagic) or systemic embolism Stroke (ischemic or hemorrhagic) or systemic embolism Stroke (ischemic or hemorrhagic) or systemic embolism Safety outcome Primary: Major Bleeding Primary: Major Bleeding Primary: Major Bleeding Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011; ENGAGE- AF Study Investigators. AHJ 2010

68 Efficacy and safety in elderly

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72 New antithrombotic therapies compared to warfarin Stroke or systemic embolism Dabigatran 150 mg b.i.d. Dabigatran 110 mg b.i.d. Rivaroxaban 20 mg o.d. Abixaban 5 mg b.i.d Favors NOAC Favors warfarin Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011

73 New antithrombotic therapies compared to warfarin Stroke of ischemic or unknown origin Dabigatran 150 mg b.i.d. Dabigatran 110 mg b.i.d. Rivaroxaban 20 mg o.d. Abixaban 5 mg b.i.d Favors NOAC Favors warfarin Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011

74 New antithrombotic therapies compared to warfarin All-cause mortality Dabigatran 150 mg b.i.d. Dabigatran 110 mg b.i.d. Rivaroxaban 20 mg o.d. Abixaban 5 mg b.i.d Favors NOAC Favors warfarin Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011

75 New antithrombotic therapies compared to warfarin Major bleeding Dabigatran 150 mg b.i.d. Dabigatran 110 mg b.i.d. Rivaroxaban 20 mg o.d. Abixaban 5 mg b.i.d Favors NOAC Favors warfarin Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011

76 New antithrombotic therapies compared to warfarin Gastrointestinal bleeding Dabigatran 150 mg b.i.d. Dabigatran 110 mg b.i.d. Rivaroxaban 20 mg o.d. Abixaban 5 mg b.i.d Favors NOAC Favors warfarin Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011

77 New antithrombotic therapies compared to warfarin Intracranial hemorrhage Dabigatran 150 mg b.i.d. Dabigatran 110 mg b.i.d. Rivaroxaban 20 mg o.d. Abixaban 5 mg b.i.d Favors NOAC Favors warfarin Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011

78 New antithrombotic therapies compared to warfarin Myocardial infarction Dabigatran 150 mg b.i.d. Dabigatran 110 mg b.i.d. Rivaroxaban 20 mg o.d. Abixaban 5 mg b.i.d Favors NOAC Favors warfarin Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011

79 ESC 2012 recommandations Choice of anticoagulant Non-valvular AF Valvular AF* Yes <65 years & lone AF (including female) No Assess risk of stroke (CHA 2 DS 2 -VASc score) VKA *Includes rheumatic valvular disease and prosthetic valves OAC therapy No antithrombotic therapy Assess bleeding risk (HAS-BLED score) Consider patient values and preferences NOAC** VKA **NOAC should be considered instead of VKA (INR 2 3) for most patients with AF. Adapted from Camm et al. Eur Heart J 2012;e-published August 2012, doi: /eurheartj/ehs253.

80 ESC 2012 recommendations Antithrombotic therapy Recommandations Class Level Antithrombotic therapy to prevent thromboembolism is recommended for all patients with AF, except in those patients (both male and female) who are at low risk (aged <65 years and lone AF), or with contraindications. I A The choice of antithrombotic therapy should be based upon the absolute risks of stroke / thromboembolism and bleeding and the net clinical benefit for a given patient. I A When patients refuse the use of any OAC (whether VKAs or NOACs), antiplatelet therapy should be considered, using combination therapy with ASA mg plus clopidogrel 75 mg daily (where there is a low risk of bleeding) or - less effectively - ASA mg daily. IIa B Camm et al. Eur Heart J 2012;e-published August 2012, doi: /eurheartj/ehs253. EU API234 Subject to local prior approval by BMS/Pfizer, as per relevant SOP and local rules, slide may be used with external audiences in local BMS/Pfizer arranged meetings

81 Recommended work chart for choosing anticoagulants 81 Mar 2013

82 Cumulative event rate (%) Primary efficacy outcome: time to first event Rivaroxaban N=2419 Enoxaparin/VKA N=2413 HR=1.12; p< (non-inferiority) Time to event (days) Number of patients at risk Rivaroxaban Enoxaparin/VKA ITT population

83 Cumulative event rate (%) Major bleeding Enoxaparin/VKA N= Time to event (days) Rivaroxaban N=2412 Number of patients at risk Rivaroxaban Enoxaparin/VKA Safety population

84 ESC 2012 guidelines: management of bleeding with new oral anticoagulants Patient on a new OAC presenting with bleeding Check haemodynamic status, basic coagulation tests to assess anticoagulation effect Minor Delay next dose or discontinue treatment Moderate Symptomatic/supportive treatment Mechanical compression Fluid replacement Blood transfusion Oral charcoal if recently ingested Very severe Consider rfviia or PCC Charcoal filtration Dabigatran only: haemodialysis Camm AJ et al. Eur Heart J 2012

85 So what have we learned?

86 conclusion 86 Mar 2013