NOAs for stroke prevention in Atrial Fibrillation: potential advantages in the elderly patients. Giancarlo Agnelli

NOAs for stroke prevention in Atrial Fibrillation: potential advantages in the elderly patients Giancarlo Agnelli Internal & Cardiovascular Medicine - Stroke Unit University of Perugia, Italy

My talk today Age as a risk factor for Afib (and related stroke) Age in the risk stratification scores Aspirin vs. VKA in the elderly patients Recent Afib trials with NOAs for stroke prevention Elderly patients in the NOAs trials: prevalence & outcome

Prevalence of AF in US or Europe 4 50-60% patients over 80% years Go et al., JAMA 2001

Age and VKA treatment for Afib Perugia University Anticoagulation Clinic II Patients: 1676 Gender Males 868 (51.8%) Females 808 (48.2%) Age* Range: 20-97 Classe età N % < 65 years 142/1675** 8.5 65-75 years 434/1675 25.9 76-79 years 307/1675 18.3 > 80 years 674/1765 40.2 > 90 years 118/1765 7.0 981 patients (58.5%)

CHADS 2 Score Risk Factor CHF / LV dysfunction 1 Hypertension 1 Age > 75 years 1 Diabetes mellitus 1 Stroke / TIA 2 Derived from risk factors identified in datasets in non-vka treated patients Gage et al. JAMA 2001

CHA 2 DS 2 VASc Score Risk Factor Score Congestive heart failure / LV dysfunction 1 Hypertension 1 Age 75 y 2 Diabetes mellitus 1 Stroke / TIA / systemic embolism 2 Vascular disease (prior myocardial infarction, peripheral artery disease or aortic plaque) 1 Age 65-74 y 1 Sex category (i.e. female gender) 1 To identify: truly low-risk patients by being more inclusive

% in Risk of Thromboembolism Category CHADS 2 & CHA 2 DS 2 VASc Score 100% 80% 60% 40% 20% 0% 17,7 61,9 20,4 CHADS 2 75,7 15,1 9,2 CHA 2 DS 2 -VASc High Risk (score 2) Intermediate Risk (score 1) Low Risk (score 0)

HAS-BLED bleeding risk score H 1 point A 1 or 2 points S 1 B 1 L 1 E 1 D 1 or 2 points Hypertension Abnormal renal and liver function Stroke Bleeding Labile INRs Age (e.g. age > 65 years) Drugs or alcohol 3 points: 3.5%/years Pisters et al., Chest 2010

BAFTA 973 people aged 75 in AF (mean age 81) Aspirin 75mg vs. Warfarin target INR 2.5 Mean follow up 2.7 years Primary outcome measure: Fatal or disabling stroke (ischemic or haemorrhagic) or other intra-cranial haemorrhage or systemic embolus Warfarin 1.8% v aspirin 3.8% RR 0.48 (0.28-0.80) NNT: 50 for 1 year p = 0.0027 Lancet Aug 2007

Cumulative hazard AVERROES: efficacy & safety Stroke/systemic embolism Bleeding events 0.05 Hazard ratio with apixaban, 0.45 (95% CI, 0.32 0.62) Apixaban Aspirin 0.04 0.03 0.02 0.01 0.00 p < 0.001 Aspirin Apixaban 0 3 6 9 12 18 No. of events (%/yr) No. of events (%/yr) Patients (n) 2,808 2,791 Major bleeding Minor bleeding 44 (1.4%) 39 (1.2%) p value 0.57 188 153 0.05 Months Connolly et al., N Engl J Med. 2011

NOACs: prevention of stroke in AFib Rely Rocket-AF Aristotle Engage Averroe

Cumulative hazard rate RELY (dabigatran) Stroke/systemic embolism Bleeding events 0.05 0.04 Warfarin Dabigatran etexilate 110 mg b.i.d. Dabigatran etexilate 150 mg b.i.d. Dabi. 110 mg (%/y) Dabi. 150 mg (%/y) Warf. (%/y) p, dabi. 110 m mg vs. warf. p, dabi. 150 mg vs warf. 0.03 Patients (n) 6,015 6,076 6,022 0.02 Severe bleeds 2.71 3.11 3.36 0.003 0.31 0.01 0.0 lifethreatening non-life threatening 1.22 1.66 1.45 1.88 1.80 1.76 < 0.001 0.56 0.037 0.47 0 0.5 1.0 1.5 2.0 2.5 Years gastrointestinal 1.12 1.51 1.02 0.43 < 0.001 Connolly et al., N Engl J Med. 2009

Cumulative event rate (%) ROCKET- AF (rivaroxaban) Stroke and non-cns embolism* Bleeding events 6 5 4 3 2 Event rate (%/year) Rivaroxaban Warfarin 1.71 2.16 Warfarin Rivaroxaban Major and clinically relevant non-major Rivaroxaban Rate (%/year) Warfarin Rate (%/year) p value 14.91 14.52 0.442 major 3.60 3.45 0.576 1 HR (95% CI): 0.79 (0.66 0.96) Non-inferiority p < 0.001 0 0 120 240 360 480 600 720 840 960 Days from randomization clinically relevant nonmajor 11.80 11.37 0.345 * Based on protocol-compliant, on-treatment population. Patel et al. N Engl J Med., 2011

ARISTOTLE: (apixaban) Stroke or systemic embolism ISTH major bleeding 21% RRR 31% RRR Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, 0.66 0.95); P=0.011 Apixaban 327 patients, 2.13% per year Warfarin 462 patients, 3.09% per year HR 0.69 (95% CI, 0.60 0.80); P<0.001 Median TTR 66%

Stroke or systemic embolic event (%) 8 6 Kaplan-Meier of primary efficacy outcome ITT population Warfarin Edoxaban 60 mg (HR=0.87, 0.73 1.04) Edoxaban 30 mg (HR=1.13, 0.96 1.34) 4 2 (TTR 68.4%) 0 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years No.at risk Warfarin 7036 6798 6615 6406 6225 4593 2333 536 Edoxaban (60)7035 6816 6650 6480 6283 4659 2401 551 Edoxaban (30)7034 6815 6631 6461 6277 4608 2358 534 Giugliano et al. N Engl J Med 2013; e-pub ahead of print

Major bleeding (%) Kaplan-Meier of principal safety outcome 12 10 8 6 4 Warfarin Edoxaban 60 mg (HR=0.80, 0.71 0.91) Edoxaban 30 mg (HR=0.47, 0.41 0.55) 2 Median TTR=68.4% 0 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years No.at risk Warfarin 7012 6166 5630 5278 4941 3446 1687 370 Edoxaban (60)7012 6039 5594 5232 4910 3471 1706 345 Edoxaban (30)7002 6218 5791 5437 5110 3635 1793 386 Giugliano et al. N Engl J Med 2013; e-pub ahead of print

NOACs: prevention of stroke in AFib Rely: 41% older than 75 years 17% older than 80 years Rocket-AF 43% older than 75 years 25% older than 80 years Aristotle 31% older than 75 years

RELY 3016 (17%) people aged 80 years 720 (4%) people aged 85 years 79 (0.45) aged 90 years Stroke & SSE 80 years Dabigatran 110 bid vs. warfarin: HR 0.68 Dabigatran 150 bid vs. warfarin: HR 0.65 ICH 80 years Dabigatran 110 bid vs. warfarin: HR 0.24 Dabigatran 150 bid vs. warfarin: HR 0.53 Lancet Aug 2007

ROCKET- AF %/year Age 75 years R N=3082 W N=3082 HR (95% CI) Age < 75 years R N=3999 W N=4088 HR (95% CI) p- value* Stroke/SE 1 2.29 2.85 0.80 (0.63-1.02) 2.00 2.10 0.95 (0.76-1.19) 0.31 Fatal/disabling stroke 1 1.14 1.50 0.76 (0.55-1.06) 0.90 1.09 0.83 (0.60-1.15) 0.72 Mortality 2 2.08 2.49 0.84 (0.64-1.07) 1.71 2.01 0.85 (0.66-1.09) 0.93 Major 4.86 4.40 1.11 (0.92-1.34) 2.69 2.79 0.964 (0.78- bleeding 3 1.19) ICH 3 0.66 0.83 0.80 (0.499-1.282) 0.34 0.37 0.68 0.54 (0.33-0.89) 0.27 CRNMB 3 15.61 13.54 1.15 (1.03-1.23) 9.22 9.87 0.94 (0.83-1.05) 0.01 R=rivaroxaban; W=warfarin; *p-value for interaction; ICH=intracerebral haemorrhage; CRNMB=clinically relevant non-major bleeding 1 ITT population, 2 safety population excluding a GCP violating site, 3 safety population Halperin JL et al. presented at AHA 2012

Subgroups: efficacy Subgroup Edoxaban Hazard Ratio with High (95% CI) Interaction p-value Hazard Ratio with Low (95% CI) Interaction p-value Patients 60 mg 30 mg Warfarin Edoxaban 60 mg vs warfarin Edoxaban 30 mg vs warfarin All Patients 21105 1.57 2.04 1.80 Age Group <75 years 75 years 12631 8474 1.35 1.91 1.71 2.55 1.48 2.31 0.59 0.87 Sex Male Female 13065 8040 1.45 1.76 1.86 2.32 1.68 2.00 0.97 0.76 Region North America Latin America Western Europe Eastern Europe Asia 4681 2661 3236 7144 3383 1.24 1.61 1.84 1.52 1.86 1.63 2.15 1.94 2.14 2.43 1.56 2.50 1.53 1.60 2.37 0.25 0.32 Race White Non-White 17067 4037 1.53 1.74 1.95 2.43 1.68 2.34 0.28 0.49 0.5 0.75 1 1.5 2 2.5 0.5 0.75 1 1.5 2 2.75 Edoxaban better Warfarin better Edoxaban better Warfarin better Giugliano et al. N Engl J Med 2013; e-pub ahead of print

Subgroups: safety Subgroup Edoxaban Hazard Ratio with High (95% CI) Interaction p-value Hazard Ratio with Low (95% CI) Interaction p-value Patients 60 mg 30 mg Warfarin Edoxaban 60 mg vs warfarin Edoxaban 30 mg vs warfarin All Patients 21026 2.75 1.61 3.43 Age Group <75 years 75 years 12594 8432 2.02 4.01 1.23 2.26 2.62 4.83 0.57 0.95 Sex Male Female 13020 8006 2.90 2.48 1.66 1.54 3.47 3.35 0.34 0.78 Region North America Latin America Western Europe Eastern Europe Asia 4665 2651 3220 7121 3369 4.07 2.65 3.26 1.44 3.51 2.57 1.66 1.40 0.99 1.87 4.47 3.74 3.98 2.17 4.12 0.50 0.35 Race White Non-White 17008 4017 2.72 2.88 1.58 1.76 3.23 4.32 0.16 0.34 0.6 0.8 1 1.2 1.4 0.2 0.3 0.4 0.6 0.8 1 Edoxaban better Warfarin better Edoxaban better Giugliano et al. N Engl J Med 2013; e-pub ahead of print

Patients with ICH (%) Phase III AF trials: intracranial hemorrhage NOAC Warfarin 2 1 P<0.001 P<0.001 P=0.02 0,74 0,74 0,70 P<0.001 0,80 P<0.001 P<0.001 0,85 0,85 0,30 0,23 0,50 0,33 0,39 0,26 0 RE-LY 150 mg RE-LY 110 mg ROCKET-AF ARISTOTLE ENGAGE 60 mg ENGAGE 30 mg 1. Connolly et al. N Engl J Med 2009;361:1139 1151; 2. Patel et al. N Engl J Med 2011;365:883 891 3. Granger et al. N Engl J Med 2011;365:981 992; 4. Giugliano et al. N Engl J Med 2013; e-pub ahead of print

Responsible use of NOAs Although safer than VKA, NOAs hold the risk of bleeding NOAs should be given for approved indications at validated doses (assessing the potential benefit in the individual patient) Patients should receive a complete information about the NOAs treatment at the start-up visit An adherence to treatment plan as well as a follow-up plan with regular visits should be set-up A hospital police to deal with bleeding complications and emergency surgery should be set-up and spread-out