1. APIXABAN NELLA SPAF 21 maggio 2015 ROMA Dott. Sergio Agosti Cardiologo, Ospedale Novi Ligure (AL) www.docvadis.it/agostisergio agostisergio@virgilio.it http://www.arcaliguria.it/ SPAF: quale ruolo ha ancora l’ASA?

2. Introduction to ASA One of the most widely used drugs of the 20th century 1 Taken by millions of patients worldwide for the treatment and prevention of CVD, and is the most widely tested antiplatelet drug 1 Has been (and is still) used for stroke prevention in AF 1,2 ASA = acetylsalicylic acid; CVD = cardiovascular disease; VKA = vitamin K antagonist 1. Dai Y, Ge J. Thrombosis 2012;2012:245037; 2. Camm AJ et al. Eur Heart J 2012;33:2719–47 2 Traditionally considered a safe, but less effective, alternative to VKAs when anticoagulation is contraindicated, or for use in patients at low risk of stroke 1,2 However, this is not consistent with the latest treatment guidelines 2

3. ASA for stroke prevention in AF AIAC and AHA/ACC Guidelines

4. ASA for stroke prevention in AF ESC Guidelines

5. ASA?? Camm AJ et al. Eur Heart J

7. NICE 2014 Guidelines on the management of AF 2 “Do not offer aspirin monotherapy solely for stroke prevention with atrial fibrillation” 2012 ESC Guidelines 1 Current Guidelines do not recommend ASA for stroke prevention in most NVAF patients 1 Camm AJ et al. Eur Heart J 2012 2 NICE clinical Guideline. 2014. The management of AF

8. Limited efficacy of ASA in reducing stroke risk in patients with AF 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;146:857–67 RRR (%) † 100–100500–50 AFASAK (1989) SPAF (1991) EAFT (1993) ESPS II (1997) ASA betterPlacebo better LASAF (1997) 125 mg/d 125 mg QOD UK-TIA (1999) 300 mg/d 1200 mg/d JAS (2006)T All trials RRR: 19%* ( 95% CI: –1 to 35%) Only the SPAF trial showed a benefit of ASA over placebo for reducing stroke risk

9. ASA was less effective than VKA in historical trials in AF 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;146:857–67 9 RRR (%) † 100–100500–50 AFASAK I (1990) BAFTA (2007) EAFT (1993) PATAF (1999) Warfarin betterASA better Chinese ATAFS (2006) SPAF II (1994) Age  75 yrs Age >75 yrs All trials (4620 pt) RRR: 38%* ( 95% CI: 18-52%)

11. Risk of major and intracranial bleeding not significantly different between ASA and OAC *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 Friberg L et al. Eur Hear J 2012:33:1500-10; Pisters R et al. Chest 2010;138:1093–100 ASA (n=61 396) Major bleeding 0 5 10 15 20 25 01234567 HAS-BLED total score* Bleeds/year 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 01234567 HAS-BLED total score* Intracranial bleeding Bleeds/year OAC (n=48 599) Tot Pt 182,678

22. B. Major Bleeding Characteristic No. of patients ASAApixabanHazard Ratio (95% CI) P value for interaction No. of events (%/yr) Overall559939 (1.2)44 (1.4) CHADS 2 score 0.70 0-120266 (0.5) 2199914 (1.3)14 (1.2) ≥ 3157019 (2.1)24 (2.9) AVERROES: endpoint principali di efficacia e sicurezza e richio di ictus Adapted from Connolly et al. N Engl J Med 2011;364:806-17. A. Stroke and Systemic Embolism Characteristic No. of patients ASAApixabanHazard Ratio (95% CI) P value for interaction No. of events (%/yr) Overall5599113 (3.7)51 (1.6) CHADS 2 score 0.23 0-1202618 (1.6)10 (0.9) 2199940 (3.7)25 (2.1) ≥ 3157055 (6.3)16 (1.9) 0.050.251.004.00 Apixaban better ASA better 0.050.251.004.00 Apixaban better ASA better

24. ASA for stroke prevention in AF AIAC and AHA/ACC Guidelines

25. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation JACC - DOI: 10.1016/j.jacc.2014.03.022

26. Raviele A et al.G Ital Cardiol 2013;14(3):215-240 RecommendationsCOR a LOE b FA with CHA2DS2-VASc score 0 No antithrombotic therapyIB FA with CHA2DS2-VASc score 1 c Warfarin (INR 2.0-3.0) or dabigatran, rivaroxaban, apixaban IIbB FA with CHA2DS2-VASc score ≥2 Warfarin (INR 2.0-3.0) or dabigatran, rivaroxaban, apixaban IA a: Class of Recommendations b: Level of evidence. c: in the category CHA2DS2-VASc score 1 there are pt with really low risk for whom is not reccomended any therapy (sex female and age <65 years) or is reccomended aspirin (cardiovascular disease). The presence of renal disfunction (creatinine clearance <60 ml/min) identifies pt at high risk for whom is indicated oral anticoagulant therapy “… The risk of stroke in the pt with CHA2DS2-VASc score = 1 is 1.3%/year. It is a not trascurable risk, but the indacation to oral anticoagulant therapy in this pt should be evaluated on the basis of clinical net benefit - balance of risks and benefits (anticoagulant therapy bleeding risk is 1.2%) 2013 AIAC Guideline for the Management of Patients With Atrial Fibrillation

27. Event rate(95%CI) of hospital admission and death due to thromboembolism per 100 person year

29. Kaplan-Meier estimate of probability of remaining free of thromboembolism with CHADS2 score 0 and 1

30. Kaplan-Meier estimate of probability of remaining free of thromboembolism with CHA2DS2-VASc score 0 and 1

31. ASA Conclusions ➢ Antiplatelet therapy should be considered only when patients refuse any OAC, or cannot tolerate OAC for reasons unrelated to bleeding, or in a specific subgroups of pt with CHADVASC 1 ➢ In the real world, antiplatelet therapy is still commonly prescribed for stroke prevention in AF ➢ Compared with ASA, NOAs (apixaban) significantly reduced the relative risk of stroke or systemic embolism by 55% while the risk of major bleeding was not significantly increased ➢ The evidence demonstrated that oral anticoagulation should be the preferred option in NVAF patients at risk of stroke