2. PROPRIETA’ GENERALI

3. INDICATIONS Apixaban is recommended as an option for preventing stroke and systemic embolism in people with nonvalvular atrial fibrillation with 1 or more risk factors such as: prior stroke or transient ischaemic attack age 75 years or older hypertension diabetes mellitus symptomatic heart failure.

4. Patients with AF who have stroke risk factor(s) ≥1 are recommended to receive effective stroke prevention therapy, which is essentially OAC The evidence for effective stroke prevention with aspirin in AF is weak, with a potential for harm The use of antiplatelet therapy … for stroke prevention in AF should be limited to the few patients who refuse any form of OAC.

5. Of the whole study population (n=6036) 46% of the patients received OAC, 37.5% 1 antiplatelet agent 16.5% received no antithrombotic therapy 44.4% of the patients who did not receive warfarin presented with valid reasons not to be treated (side effects, refusal, no compliance, risk of bleeding) Am J Cardiol 2013

6. A study comparing the safety and efficacy of apixaban and aspirin in patients with AF 5600 patients with AF unsuitable for or intolerant of warfarin Randomized to 5 mg of apixaban or 81 to 324 mg of aspirin for up to 36 months or until end of study Primary efficacy outcome: time from the first dose of the study drug to the first occurrence of ischemic stroke, hemorrhagic stroke, or systemic embolism Secondary efficacy outcome: time to the first occurrence of ischemic stroke, hemorrhagic stroke, systemic embolism, MI, or vascular death S Connolly (McMaster UCongressniversity, Hamilton, ON) AVERROES (Apixaban versus Acetylsalicylic Acid to Prevent Strokes) AF=atrial fibrillation

8. Warfarin (target INR 2-3) Apixaban 5 mg oral twice daily (2.5 mg BID in selected patients) Primary outcome: stroke or systemic embolism Hierarchical testing: non-inferiority for primary outcome, superiority for primary outcome, major bleeding, death Randomize double blind, double dummy (n = 18,201) Inclusion risk factors  Age ≥ 75 years  Prior stroke, TIA, or SE  HF or LVEF ≤ 40%  Diabetes mellitus  Hypertension Inclusion risk factors  Age ≥ 75 years  Prior stroke, TIA, or SE  HF or LVEF ≤ 40%  Diabetes mellitus  Hypertension Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device Major exclusion criteria  Mechanical prosthetic valve  Severe renal insufficiency  Need for aspirin plus thienopyridine Major exclusion criteria  Mechanical prosthetic valve  Severe renal insufficiency  Need for aspirin plus thienopyridine ARISTOTLE Atrial Fibrillation with at Least One Additional Risk Factor for Stroke

9. Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, 0.66–0.95); P (superiority)=0.011 No. at Risk Apixaban912087268440605134641754 Warfarin908186208301597234051768 P (non-inferiority)<0.001 21% RRR

10. Major Bleeding ISTH definition 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 No. at Risk Apixaban908881037564536530481515 Warfarin905279107335519629561491 31% RRR

12. 6 Strokes 15 Major bleeds 8 Deaths Compared with warfarin, apixaban (over 1.8 years) prevented per 1000 patients treated. 4 hemorrhagic 2 ischemic/uncertain type ARISTOTLE

13. Jama neurology 2013

14. RENAL FAILURE Hohnloser et al, European Heart Journal 2012

15. COST-EFFECTIVENESS The Committee concluded that : apixaban had been shown to be cost effective compared with warfarin, the most plausible ICER being less than £20,000 per QALY gained, and could be recommended as an option for preventing stoke and systemic embolism for people with nonvalvular atrial fibrillation who have 1 or more risk factors for stroke. there was insufficient evidence to distinguish between the cost effectiveness of apixaban, dabigatran and rivaroxaban at this time. NICE technology appraisal guidance 275

16. UNCERTAINTY TRANSIENT ISCHAEMIC ATTACK HEALTH-RELATED QUALITY OF LIFE NO ADVANTAGE ON GASTROINTESTINAL BLEEDING NO DATA ON CARDIOVERSION

17. Piano terapeutico

18. PIANO TERAPEUTICO 2

19. URGENZE EMORRAGIA: -NON ESISTE ANTIDOTO -CARBONE VEGETALE -PLASMA FRESCO CONGELATO -FATTORE VIIa SOVRADOSAGGIO: -50 mg/DIE X 7GG :NESSUN PROBLEMA -CARBONE : RIDUZIONE AUC DEL 50%

24. In the population for whom warfarin was suitable, the ICER for apixaban compared with warfarin was £12757 per QALY gained. in a population for whom warfarin was unsuitable apixaban was associated with an ICER of £2903 per QALY gained compared with aspirin.

25. ARISTOTLE

26. Potente inibitore, reversibile, diretto e altamente selettivo del sito attivo del fattore Xa libero e legato Non necessita dell'antitrombina III per esercitare l'attività antitrombotica; non ha effetti diretti sull'aggregazione piastrinica, ma inibisce indirettamente l'aggregazione piastrinica indotta dalla trombina. L'attività anti-Xa è, a diverse dosi, in rapporto lineare diretto con la concentrazione plasmatica, raggiungendo i valori massimi allo steady- state APIXABAN (Eliquis®).