Apixaban dalle evidenze cliniche al mondo reale

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1 Apixaban dalle evidenze cliniche al mondo reale Ruggiero Mango Servizio di Ecocardiografia ASL RMB Dipartimento di Emergenze Sezione di Cardiologia Interventistica Università degli Studi di Roma Tor Vergata

2 History of Anticoagulation

3 History of Warfarin discovery 1933 Cattle dying of internal bleeding with no precipitating cause > Sweet clover disease Research work funded by the: Wisconsin Alumni Research Foundation Patented in 1941 (Karl Link ) Variation of dicoumarol (warfarin) patented as rat poison in 1948 It gained fame when it was used to treat President Dwight D. Eisenhower after his 1955 coronary event while in office

4 LIMITS OF WARFARIN Delayed onset of action Large interindividual variability in response Unpredictable pharmacokinetic characteristics (PK) Drug-drug interactions SNPs in genes affecting metabolism and PD Intensive monitoring using international normalized ratio (INR) and frequent dose adjustments to provide adequate anticoagulation Up to 50% of patients will not achieve a stable INR Food restriction Gong et al Canad J Card; 2013

5 Therapeutic Range for Warfarin: INR Values at Stroke or ICH WARNING STROKE Therapuetic window WARNING BLEEDING Fuster J Am Coll Cardiol. 2001;38:

6 History of anticoagulant evolution

7 NOAC Phase III Trials Timelines

8 NOACs Advantages Significant effort has been made to develop new OACs (NOACs) with direct mechanisms of action with a sufficiently wide therapeutic window to allow for fixed-dose administration without the need for routine response monitoring (Gong et al 2013) Pro-drug

9 Point of action of NOACs in the coagulation cascade

10 All NOACs

11 FARMACODINAMICA FARMACOCINETICA

12 Plasma concentration profiles of dabigatran, rivaroxaban, and apixaban in atrial fibrillation patients Plasma concentration profiles of dabigatran, rivaroxaban, and apixaban in atrial fibrillation patients. Gong et al 2013

13 APIXABAN EFFICACY IN STROKE REDUCTION

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15 ALL NOACs: STROKE OR SE Ruff CT et al. lancet 2014

16 NOAC vs. warfarin: ictus emorragico 1. Connolly et al. NEJM 2010;363:1875-6, suppl app. 2. Patel et al. NEJM 2011

17 ALL NOACs: ALL STROKES 1. Connolly et al. NEJM 2010;363:1875-6, suppl app. 2. Patel et al. NEJM 2011

18 APIXABAN SAFETY Major and GI bleeding

19 NOAC vs. warfarin: major bleeding 1. Connolly et al. NEJM 2010;363:1875-6, suppl app. 2. Patel et al. NEJM 2011

20 NOAC vs. warfarin: GI bleeding 1. Connolly et al. NEJM 2010;363:1875-6, suppl app. 2. Patel et al. NEJM 2011

21 APIXABAN ELDERLY AND KIDNEY DISFUNCTION

22 SAFETY AND EFFICACY IN ELEDERLY (>75 YO) *p<0.001 vs warfarin; HR, hazard ratio; CI, confidence interval; ICH, intracranial haemorrhage; SE, systemic embolism.

23 porto all età nella prevenzione dell ictus in pazienti con FA: o

24 Efficacia e sicurezza di apixaban vs warfarin in relazione alla funzione renale in pazienti con FA: osservazioni dello studio clinico ARISTOTLE per la prevenzione di ictus o embolia sistemica è risultata costante, a pre

25 NOAC vs. warfarin ALL CAUSE OF DEATH CV DEATH 1. Connolly et al. NEJM 2010;363:1875-6, suppl app. 2. Patel et al. NEJM 20

26 Apixaban is the only oral anticoagulant to demonstrate superiority vs. warfarin in all of the following 3 outcomes

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28 Apixaban 5 mgx2/die risulta come il farmaco che presenta il miglior profilo in termini di bilanciamento tra efficacia e sicurezza Dabigatran 150 mg, mentre da un lato presenta un buon dato di efficacia, dall altro è penultimo per sicurezza Dabigatran 110 mg è penultimo per efficacia e in mezzo alla classifica per sicurezza Rivaroxaban 20 mg è in mezzo alla classifica per efficacia e ultimo per

29 How much Under dosing of oral anticoagulants is common? Did the dose reduction work?

30 AF increases the risk of ischaemic stroke by 5 fold and is associated with 15% of strokes for all age groups and 30% in persons over the age of 80 years AF-related stroke patients have higher recurrent risk, morbidity, and mortality as compared to patients with other stroke types The use of VKAs reduces stroke/systemic embolism by 64% and all-cause mortality by 26%, compared to control or placebo

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32 Beneficio clinico netto degli anticoagulanti orali non AVK rispetto a warfarin in studi clinici di fase III sulla FA NAO VS WARFARIN: ICTUS Nei quattro studi analizzati, apixaban apparentemente conferisce la maggiore ISCHEMICO, ICTUS EMORRAGICO, riduzione del rischio (il più basso numero INFARTO MIOCARDICO, EMBOLIA necessario al trattamento) nella SISTEMICA, SANGUINAMENTI MAGGIORI AGGIUSTATI prevenzione dell outcome composito pesato di ictus ischemico + embolia sistemica + infarto miocardico + ictus emorragico + sanguinamento maggiore aggiustato Renda G, di Nicola M, De Caterina R. Am J Med 2015; 128(9): e2

33 Moving the Tipping Point The Decision to Anticoagulate Patients With Atrial Fibrillation 1,7% < 0.2% per year no antithrombotic therapy is preferred > 1.7% per year anticoagulation with warfarin is best between 0.2% and 1.7% per year, aspirin is preferred Eckman et al, Circ Cardiovasc Qual Outcomes 2010

34 0,9%

35 CHA2DS2-VASc =1 [male], =2 [female] European registry: one-year stroke rate of 1.55%/year 0.96%/year (primary discharge diagnoses of ischemic stroke and with full follow-up) Apostolakis S et al., Int J Cardiol 2013 Large studies on Asian populations showed that the incidence of this complication may be significantly higher ( 2%/year). Patti et al., Heart Rhythm Major Bleeding Apixaban Warfarin Intracranial Bleeding Lopes RD et al., Lancet 2012

36 Net clinical benefit of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus no treatment in a real world atrial fibrillation population: A modelling analysis based on a nationwide cohort study In patients with CHADS2=0 but at high bleeding risk, apixaban and dabigatran 110 mg bid have a positive net clinical benefit. At CHA2DS2-VASc=1, apixaban and both doses of dabigatran (110 mg and 150 mg bid) have a positive net clinical benefit. In patients with CHADS2 score 1 or CHA2DS2-VASc 2, the three new OACs appear superior to warfarin for net clinical benefit, regardless of risk of bleeding. When risk of bleeding and stroke are both high, all three new drugs appear to have a greater net clinical benefit than warfarin. Banerjee et al.,thrombosis and Haemostasis 107.3/2012

37 There is no doubt in my mind that when clinicians discuss anticoagulation with their AF patients with a CHA2DS2-VASc risk score of 1, the bar has been lowered; more patients will receive anticoagulant therapy, and many strokes will be prevented. Hugh Grosvenor Calkins, M.D.

38 CONCLUSIONI: APIXABAN Potente inibitore del FXa E il più selettivo (Ki 0.08 nm) Non risente dell assunzione del cibo Profilo sicuro in pazienti con IRC e anziani Profilo bilanciato efficacia/sicurezza soprattutto in termini di riduzione dei sanguinamenti maggiori

39 Thank you for your attention! La scienza non è altro che buon senso addestrato e organizzato. Thomas H. Huxley