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EUAPI581c, April 2014 The use of ELIQUIS (apixaban) in various clinical populations Full Prescribing Information is provided at the end of this presentation 15.ELI.22.7 43NL15PR04120-01 Slide 2 ELIQUIS (apixaban) has demonstrated superiority vs warfarin in the following three key outcomes 1 1. Granger et al. N Engl J Med 2011;365:98192. Adapted from Granger et al. N Engl J Med 2011;365:98192. 3.94% 669/9,081 3.52% 603/9,120 3.09% 462/9,052 2.13% 327/9,088 1.60% 265/9,081 1.27% 212/9,120 Median duration of follow-up 1.8 years Superior stroke / systemic embolism prevention Superior profile in reducing major bleeding Superior reduction in all-cause mortality 21% RRR p=0.01 31% RRR p Introduction on sub analyses The overall outcomes of a study provide the best evidence for the direction of the effect of two interventions in an RCT Subgroup analyses assess the consistency of the outcomes in a subgroup with the overall trial results Tests for interaction between treatment and subgroup are key to assess the statistical relevance of the outcome in a subgroup 1 If p-value for interaction is not significant (p>0.05), the results in the subgroup can be considered as consistent with the results in the overall population 1 1. Rothwell. Lancet 2005;365:17686. RCT: randomized controlled trial Slide 4 The efficacy and major bleeding results of ELIQUIS vs warfarin in key subgroups in ARISTOTLE were consistent with the overall trial results 1 ELIQUIS (apixaban) has clinical benefits over warfarin that are maintained irrespective of renal function 2 that are maintained irrespective of age 3 that are consistent across patient risk of stroke and bleeding as assessed by the CHADS 2, CHA 2 DS 2 -VASc, and HAS-BLED risk scores 4 1. Apixaban SmPC. Available at http://www.ema.europa.eu; 2. Hohnloser et al. Eur Heart J 2012;22:282130; 3. Halvorsen et al. Eur Hear J 2014. Feb 20 [epub ahead of print]; 4. Lopes et al. Lancet 2012;380:174958. Slide 5 Chronic kidney disease is common among AF patients 1. Kooiman et al. J Thromb Haemost 2011;9:16523; 2. Jnsson et al. Thromb Res 2011;128:3415. Leiden Anticoagulation Clinic (n=5,039; 19972005) 1 % of Patients 65.8% 100 80 60 40 0 30.9% 20 eGFR, mL/min/1.73 m 2 (MDRD formula) 2.5% >6030601530015 34.2% 0.8% Adapted from Kooiman et al. J Thromb Haemost 2011;9:16523. 40.4% 16.3% % of Patients 100 80 60 40 0 20 4.3% 80 mL/min 7,587 patients (42%) had an eGFR of >50 80 mL/min 3,017 patients (15%) had an eGFR of 50 mL/min Patients with severe renal insufficiency (calculated creatinine clearance ofSlide 9 ApixabanWarfarin Hazard Ratio (95% CI) p value for interaction %/yr (No. of Events) Stroke / SE0.705 eGFR >80 mL/min 1 0.99% (70)1.12% (79) eGFR >50-80 mL/min 2 1.24% (87)1.69% (116) eGFR 50 mL/min 3 2.11% (54)2.67% (69) Major bleeding0.03 eGFR >80 mL/min 1 1.46% (96)1.84% (119) eGFR >50-80 mL/min 2 2.45% (157)3.21% (199) eGFR 50 mL/min 3 3.21% (73)6.44% (142) All-cause death0.627 eGFR >80 mL/min 1 2.33% (169)2.71% (195) eGFR >50-80 mL/min 2 3.41% (244)3.56% (251) eGFR 50 mL/min 3 7.12% (188)8.30% (221) ELIQUIS (apixaban) was more effective and was associated with less major bleeding events than warfarin irrespective of renal function 1 1. Hohnloser et al. Eur Heart J 2012;22:282130. 0.250.51.002.0 Apixaban Better Warfarin Better 1 n=7,518 (41%); 2 n=7,587 (42%); 3 n=3,017 (17%) Results were consistent regardless of methods for GFR estimation Adapted from Hohnloser et al. Eur Heart J 2012;22:282130. Slide 10 ELIQUIS (apixaban) was more effective & was associated with less major bleeding events than warfarin in patients with impaired renal function 1 1. Hohnloser et al. Eur Heart J 2012;22:282130. Baseline Cockcroft-Gault eGFR mL/min p value for interaction: 0.57 Baseline Cockcroft-Gault eGFR mL/min p value for interaction: 0.005 Stroke or Systemic Embolism Major Bleeding Adapted from Hohnloser et al. Eur Heart J 2012;22:2821-30. Warfarin95% CI Apixaban95% CI 1-year Event Rate Slide 11 How to use ELIQUIS (apixaban) in patients with renal impairment 1. Apixaban SmPC. Available at http://www.ema.europa.eu Impaired renal function SmPC recommendation Mild or moderate renal impairment No dose adjustment required unless the patient fulfils criteria for dose reduction* to 2.5 mg twice-daily based on age, body weight and/or serum creatinine 1 Severe renal impairment (creatinine clearance 15-29 mL/min) Dose reduction to 2.5 mg twice-daily 1 DialysisNot recommended 1 Renal failure (creatinine clearanceSlide 12 Question 2 Imagine this patient*: Female Permanent NVAF: was on aspirin and wants to be put on OAC Age: 75 years Hypertension Creatinine clearance 75 ml/min Would you treat this patient with ELIQUIS (apixaban)? 1. Yes 2. No *Patient is fictitious Slide 13 Age distribution in ARISTOTLE 1 The risk of stroke in atrial fibrillation increases with age 1 Warfarin is particularly underused in elderly patients 2,3 1. Halvorsen et al. Eur Hear J 2014.Feb 20 [epub ahead of print]; 2. Hylek et al. Circulation 2007;115:268996; 3. Waldo et al. J Am Coll Cardiol 2005;46:172936. 30% 39% 31% n = 18,201 Range 19-100 yrs 2,436 patients (13%) were 80 yrs Adapted from Halvorsen et al. Eur Hear J 2014;Feb 20 [epub ahead of print]. Patient number Slide 14 ICH: Intracranial haemhorrage; SE: systemic embolism Adapted from Halvorsen et al. Eur Hear J 2014. Feb 20 [epub ahead of print]. In the ARISTOTLE trial, age was a risk factor for various efficacy and safety outcomes 1 1. Halvorsen et al. Eur Hear J 2014. Feb 20 [epub ahead of print]. Stroke /SE Major bleeding Death ICH Primary outcomes in the elderly (75 years) in relation to renal function 1 1. Halvorsen et al. Eur Hear J 2014. Feb 20 [epub ahead of print]. Subgroup No. of patients 75 years ApixabanWarfarin Hazard Ratio (95% CI) p value for interaction * No. of events (%/yr) Stroke or systemic embolism0.4954 eGFR >80 mL/min5978 (1.41)11 (2.16) 0.65 (0.26, 1.62) eGFR >50-80 mL/min2,92239 (1.45)45 (1.70) 0.86 (0.56, 1.32) eGFR >30-50 mL/min1,90628 (1.74)44 (2.69) 0.65 (0.40, 1.04) eGFR 30 mL/min2223 (1.70)9 (5.57) 0.29 (0.08, 1.07) Major bleeding0.1635 eGFR >80 mL/min59611 (2.10)15 (3.39) 0.6 (0.28, 1.32) eGFR >50-80 mL/min2,91285 (3.53)104 (4.45) 0.79 (0.60, 1.06) eGFR >30-50 mL/min1,89847 (3.32)87 (6.27) 0.53 (0.37, 0.76) eGFR 30 mL/min2217 (4.64)17 (13.4) 0.35 (0.14, 0.86) eGFRs according to Cockcroft-Gault method * Interaction P-values are based on categorical eGFR Adapted from Halvorsen et al. Eur Hear J 2014;Feb 20 [epub ahead of print]. Slide 19 Question 3 Imagine this patient*: 68 year old male Newly diagnosed with asymptomatic, paroxysmal NVAF Hypertension: blood pressure 145 / 92 mmHg Anaemia Regularly uses ibuprofen for back pain CHADS 2 score = 1; CHA 2 DS 2 -VASc score = 2; HAS-BLED score = 3 Would you treat this patient with ELIQUIS (apixaban)? 1. Yes 2. No *Patient is fictitious Slide 20 Many stroke risk factors are also risk factors for bleeding Higher stroke risk = higher bleeding risk (overlapping factors) The relationship between stroke risk and bleeding risk complicates the evaluation of benefit-risk 1. Lip et al. Chest 2010;137:26372; 2. Pisters et al. Chest 2010;138:1093100. CHA 2 DS 2 -VASc criteria 1 Congestive heart failure/LV dysfunction Hypertension Aged 75 years Diabetes mellitus Stroke/TIA/TE Vascular disease (prior MI, PAD, or aortic plaque) Aged 65-74 years Sex category (i.e. female gender) HAS-BLED criteria 2 Hypertension Abnormal renal / liver function Stroke Bleeding Labile INRs Elderly (above 65 years) Drugs or alcohol LV: left ventricle; TE: thromboembolism; TIA: transient ischemic attack; VKA: vitamin K antagonist; PAD: peripheral arterial disease Slide 21 ARISTOTLE enrolled patients across a broad range of stroke and bleeding risk 1 Patients with non-valvular AF and at least 1 risk factor for stroke were enrolled 1 CHADS 2 and HAS-BLED scores were correlated in ARISTOTLE: 2 1. Granger et al. N Engl J Med 2011;365:98192; 2. Lopes et al. Lancet 2012;380:174958. HAS-BLED score 0-123Total CHADS 2 score 13,203 (18%)2,051 (11%)929 (5%)6,183 (34%) 22,807 (15%)2,461 (14%)1,248 (7%)6,516 (36%) 31,451 (8%)2,056 (11%)1,995 (11%)5,502 (30%) Total7,461 (41%)6,568 (36%)4,172 (23%)18,201 (100%) Adapted from Lopes et al. Lancet 2012;380:174958. Slide 22 ApixabanWarfarin Hazard Ratio (95% CI) p value No. of patients %/yr (No. of events) CHADS 2 Interaction: 0.4457 16,1830.74% (44)0.87% (51) 26,5161.24% (74)1.37% (82) 35,5021.95% (94)2.80% (132) CHA 2 DS 2 VASc Interaction: 0.1210 11,6040.62% (10)0.53% (8) 23,7710.85% (30)0.67% (24) 312,8261.48% (172)2.03% (233) HAS-BLED Interaction: 0.9422 017,4610.92% (65)1.14% (79) 26,5681.39% (83)1.81% (109) 34,1721.73% (64)2.14% (77) Overall18,2011.27% (212)1.60% (265) 0.0144 Favours apixabanFavours warfarin ARISTOTLE Stroke or systemic embolism according to baseline risk scores 1 1. Lopes et al. Lancet 2012;380:174958. 0.250.501.002.004.00 Adapted from Lopes et al. Lancet 2012;380:174958. Slide 23 ApixabanWarfarin Hazard Ratio (95% CI) p value No. of patients %/yr (No. of events) CHADS 2 Interaction: 0.4018 16,1691.38% (76) 2.34% (126) 26,4922.30% (125) 3.03% (163) 35,4792.88% (126) 4.15% (173) CHA 2 DS 2 VAScInteraction: 0.2059 11,6020.80% (12) 1.21% (17) 23,7591.26% (42) 2.48% (82) 312,7792.60% (273) 3.55% (363) HAS-BLEDInteraction: 0.7127 017,4331.36% (89) 2.16% (137) 26,5442.25% (123) 3.23% (175) 34,1633.46% (115) 4.70% (150) Overall18,1402.13% (327) 3.09% (462)60 kg16,154177 (1.2)212 (1.4) Type of AF Permanent/Persistent15,412191 (1.4)235 (1.7) 0.70 Paroxysmal2,78621 (0.8)30 (1.1) Prior stroke or TIA Yes3,43673 (2.5)98 (3.2) 0.71 No14,765139 (1.0)167 (1.2) Diabetes mellitus Yes4,54757 (1.4)75 (1.9) 0.71 No13,654155 (1.2)190 (1.5) Primary efficacy results for apixaban were consistent across pre-specified major subgroups in ARISTOTLE 1 1. Granger et al. N Engl J Med 2011;365:98192. Warfarin better 0.250.501.002.00 Apixaban better Primary efficacy endpoint: stroke or systemic embolism Adapted from Granger et al. N Engl J Med 2011;365:98192. Slide 26 Primary safety results for apixaban were consistent across pre-specified major subgroups in ARISTOTLE 1 1. Granger et al. N Engl J Med 2011;365:98192. Adapted from Granger et al. N Engl J Med 2011;365:98192. Characteristics No. of patients ApixabanWarfarinHazard Ratio (95% CI) p value for interaction No. of events (%/yr) All patients 18,140327 (2.13)462 (3.09) Prior warfarin/VKA Yes10,376185 (2.1)274 (3.2) 0.50 No7,764142 (2.2)188 (3.0) Age < 65 yrs5,45556 (1.2)72 (1.5) 0.64 65 to < 75 yrs7,030120 (2.0)166 (2.8) 75 yrs5,655151 (3.3)224 (5.2) Sex Male11,747225 (2.3)294 (3.0) 0.08 Female6,393102 (1.9)168 (3.3) Weight 60 kg1,97836 (2.3)62 (4.3) 0.22 > 60 kg16,102290 (2.1)398 (3.0) Type of AF Permanent/Persistent15,361283 (2.2)402 (3.2) 0.75 Paroxysmal2,77644 (1.9)60 (2.6) Prior stroke or TIA Yes3,42277 (2.8)106 (3.9) 0.71 No14,718250 (2.0)356 (2.9) Diabetes mellitus Yes4,526112 (3.0)114 (3.1) 0.003 No13,614215 (1.9)348 (3.1) 0.250.501.002.00 Apixaban better Warfarin better Slide 27 ARISTOTLE subanalyses to date 1. Garcia et al. Am Heart J 2013;0:1-10; 2. Alexander et al. Am Heart J 2013 Sep;166(3):559-65; 3. Alexander et al. Eur Heart J 2014;35:224232; 4. Flaker et al. J Am Coll Cardiol 2013; doi: 10.1016/j.jacc.2013.09.062 ; 5. Bahit et al. Int J Cardiol 2013;170(2):215-20; 6. Hijazi et al. Circulation 2014;129(6):625-34; 7. Easton et al. Lancet Neurol 2012;11(6):503-11; 8. Hohnloser et al. Eur Heart J 2012;33(22):2821-30; 9. Lopes et al. Lancet 2012;380(9855):1749-58; 10. Hijazi et al. J Am Coll Cardiol 2013;61(22):2274-84; 11. McMurray et al. Circ Heart Fail 2013;6(3):451-60; 12. Al-Khatib et al. Eur Heart J 2013;34(31):2464-71; 13. Wallentin et al. Circulation 2013;127:2166-76; 14. Hijazi et al. J Am Coll Cardiol 2014;63(1):52-61; 15. Halvorsen et al. Eur Heart J 2014 [Epub ahead of print]; 16. Flaker et al. Poster presented at ACC Congress 2013. 17. Hylek et al. J Am Coll Cardiol. 2014. pii: S0735-1097(14)013862. TopicAuthor/year Warfarin nave/experienced Garcia et al. 2013 1 Drug dosing errorsAlexander et al. 2013 2 Concomitant ASA treatment Alexander et al. 2014 3 CardioversionFlaker et al. 2013 4 Prior MI/coronary artery disease Bahit et al. 2013 5 Biomarker hs-troponin IHijazi et al. 2014 6 Previous stroke/TIAEaston et al. 2012 7 Renal functionHohnloser et al. 2012 8 CHADS 2 /CHA 2 DS 2 VASc/HAS -BLED Lopes et al. 2012 9 TopicAuthor/year Biomarker NT-proBNPHijazi et al. 2013 10 Heart failure McMurray et al. 2013 11 Type of AF Al-Khatib et al. 2013 12 TTR/INR Wallentin et al. 2013 13 Biomarker hs-troponin THijazi et al. 2014 14 Age Halvorsen et al. 2014 15 Concomitant amiodarone treatment Flaker et al. 2013 16 Major bleedingHylek et al. 2014 17 ASA: aspirin; CAD: coronary artery disease; TTR: time in therapeutic range Slide 28 AVERROES subanalyses to date 1. Flaker et al. Stroke 2012;43(12):3291-7; 2. Diener et al. Lancet Neurol 2012;11(3):225-31; 3. Eikelboom et al. J Stroke Cerebrovasc Dis 2012;21(6):429-35; 4. Lip et al. Circ Arrhythm Electrophysiol 2013;6:31-38; 5. Hohnloser et al. Eur Heart J 2013;34(35):2752-9; 6. Coppens et al. Eur Heart J 2014;Feb 25 [epub ahead of print] TopicAuthor/year BleedingFlaker et al. 2012 1 Previous stroke / TIADiener et al. 2012 2 Renal functionEikelboom et al. 2012 3 CHADS 2 /CHA 2 DS 2 -VAScLip et al. 2013 4 HospitalizationsHohnloser et al. 2013 5 Previous VKA treatmentCoppens et al. 2014 6 Slide 29 The efficacy and major bleeding results of ELIQUIS vs. warfarin in key subgroups in ARISTOTLE were consistent with the overall trial results 1 ELIQUIS (apixaban) has clinical benefits over warfarin that are maintained irrespective of renal function 2 that are maintained irrespective of age 3 that are consistent across patient risk of stroke and bleeding as assessed by the CHADS 2, CHA 2 DS 2 -VASc, and HAS-BLED risk scores 4 1. Apixaban SmPC. Available at http://www.ema.europa.eu; 2. Hohnloser et al. Eur Heart J 2012;22:282130; 3. Halvorsen et al. Eur Hear J 2014. Feb 20 [epub ahead of print]; 4. Lopes et al. Lancet 2012;380:174958. Slide 30 ELIQUIS (apixaban) 2.5 mg & 5 mg FILM-COATED TABLETS PRESCRIBING INFORMATION SMPC link, click here