Congresso Interregionale A.R.C.A. del Nord NAO: vi sono reali vantaggi rispetto al Warfarin? Dott. Sergio Agosti Dirigente Medico SOC Cardiologia Ospedale Novi Ligure Genova, 23-24 Ottobre 2015

Assume that NAOs have been on the market for 5 year A new drug comes to the market. Compared to NAOs, the new drug has: - cheaper - antidote - requirement for monthly monitoring to adjust dose - many food and drug interactions - 25% increased relative risk of stroke/systemic embolism - nearly 50% increased relative risk of major bleeding - approx. 2.5 times the rate of ICH - 10% increased relative risk of mortality Would Warfarin be approved by regulatory authorities now?

A new era of anticoagulation? The king is dead WOULD WARFARIN BE APPROVED TODAY? Diener H-C et al. Int J of Stroke: Vol 7, February 2012, 139–141

Lancet, published online December 4, 2013

STROKE OR SYSTEMIC EMBOLISM NNT 173 Ruff CT, Lancet, December 4, 2013

MAJOR BLEEDING Ruff CT, Lancet, December 4, 2013

EFFICACY AD SAFETY SECONDARY ENDPOINTS NNT PER ICH è 140 ICH NNT 141 Ruff CT, Lancet, December 4, 2013

Haemorrhagic stroke Intracranial hemorrhage risk with the new oral anticoagulants: a systematic review and meta analysis Daniel Caldeira et al. J Neurol 2014

Haemorrhagic stroke (TF receptor) Tissue factor (TF) is a transmembrane receptor for Factor VII/VIIa (FVII/VIIa). It is constitutively expressed by cells surrounding blood vessels. The endothelium physically separates this potent "activator" from its circulating ligand FVII/FVIIa and prevents inappropriate activation of the clotting cascade. Breakage of the endothelial barrier leads to exposure of extravascular TF and rapid activation of the clotting cascade. TF is also expressed in certain tissues, such as the heart and brain, and provides additional hemostatic protection to these tissues. Il Fattore tissutale, noto più propriamente come Tissue Factor (TF) ed altrimenti indicato come fattore III o CD142, è una glicoproteina presente nel tessuto subendoteliale, nelle piastrine, e nei leucociti necessaria per la formazione della trombina dal suo zimogeno: la protrombina. La formazione della trombina porta alla coagulazione del sangue. Il tissue factor non va confuso con la tromboplastina, che è infatti un estratto tissutale composto quasi esclusivamente da TF e fosfolipidi anionici. Le diverse tromboplastine in commercio, che differiscono in termini di attività pro-coagulante, sono comunemente utilizzate in laboratorio per effettuare test di screening dell'emostasi. Mackmann, Anesth Analg. 2009 May; 108(5):1447-52 The role of tissue factor and factor VIIa in hemostasis.

Antidoto http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm467300.htm

In which patients Elderly patients Patients with renal insufficiency Patients with valvular atrial fibrillation No classificazioni, ma portiamo l’attenzione sul medico e cosa fa di fronte a det categorie di pz, sulle quali tra l’altro si gioca la vera partita dei nao

NOA in Elderly patients

Risk of non prescription of OAC by age Il rischio di stroke nella FA aumenta con l’età Warfarin è particolarmente sottoutilizzato nei pazienti anziani

NAO vs Warfarin nei pazienti > 75 anni MAJOR BLEEDING J. Am Geriatr. Soc. 2014 May; 62: 857-64. NAO in elderly adults: evidence from a meta-analysis of randomized trials. Sardar P, Lip G.

NAO vs Warfarin nei pazienti > 75 anni STROKE OR SE J. Am Geriatr. Soc. 2014 May; 62: 857-64. NAO in elderly adults: evidence from a meta-analysis of randomized trials. Sardar P, Lip G.

NOA in patients with renal insufficiency

Chronic kindney disease is common among AF patients The advantages of these agents are convenient oral dosing, predictable pharmacokinetics, avoidance of routine coagulation monitoring, noninferior or superior efficacy and acceptable safety, including a lower risk of intracranial hemorrhage Kooiman et al. J Thromb Haemost 2011;9:1652–3

Chronic kindney disease increases the risk of stroke, bleeding, and all-cause death in AF patients Olesen et al. N Engl J Med 2012;367:625–35.

Xa inhibitors are eliminated from the body via multiple routes

NAO vs Warfarin nei pazienti con IR moderata MAJOR BLEEDING Novel Oral Anticoagulants in Patients With Renal Insufficiency: A Meta-analysis of Randomized Trials. Partha Sardar et al, Can. J Cardiol. 2014; Aug, 30: 888-97.

NAO vs Warfarin nei pazienti con IR moderata STROKE OR SE Novel Oral Anticoagulants in Patients With Renal Insufficiency: A Meta-analysis of Randomized Trials. Partha Sardar et al, Can. J Cardiol. 2014; Aug, 30: 888-97.

Raccomandazioni dell’ESC nei pazienti con IR

Raccomandazioni dell’EHRA nei pazienti con IR (2015)

Cambiamento della GFR in pt con D110, D150 o Warfarin -1 -2 -3 -4 Change from Baseline 3 6 9 12 15 18 21 30 24 27 Months *p< 0.005 vs warfarin * * DE 110mg bid DE 150mg bid Warfarin * Available patients 3 months 6 months 12 months 24 months 30 months DE 110mg bid 5130 5000 4686 3368 1672 DE 150mg bid 5171 5005 4696 3434 1685 Warfarin 5243 5146 4895 3519 1703 Michael Böhm, ESC 2014, Barcelona, 30 Aug - 3 Sep 2014

Backgroun: Vitamin K-Antagonists Induce Vascular Damage Price et al, Arterioscler Thromb Vasc Biol 18 (1998): 1400-1407 Schurgers et al, Blood 109 (2007): 2823-2831 Brodsky et al, Kidney Int 109 (2011): 181-189 Krüger et al, Arterioscler Thromb Vasc Biol 33 (2013): 2618-2624

NOA in patients with valvular atrial fibrillation

Definition of non valvular atrial fibrillation (NVAF) Updated EHRA Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with NVAF: Heidbuchel, August 31, 2015

NAO in numeri…. 180000 pz nei trials 6200 articoli - studi clinici (PUBMED) Almeno 300000 pz nei registri Dabigatran è Anticoagulante che ha più analisi post hoc, registri e articoli e pz trattati nel mondo…. Oltre 18 milioni di pz trattati nel mondo

Real world data

Prescrizione inappropriata Due importanti problemi nell’interpretazione dei dati provenienti dal mondo reale (registri e studi osservazionali) Selection bias Prescrizione inappropriata Selection bias: pz con maggiore o minore rischio ischem o emorr verso i trial Prescrizione inappropriata: pazienti arruolati che non avevano indicazione a nao o che la avevano ma a dosaggio diverso… quindi alcuni ictus o emorragie potevano essere evitati

Dopo i trial registrativi, i dati di sorveglianza post-marketing vengono tenuti in grande considerazione negli Stati Uniti, in quanto ritenuti vicini alla real practice.Come avevamo anticipato in una news pubblicata nel maggio scorso, l’FDA aveva allora emanato un comunicato in cui venivano riportati alcuni dati post-marketing di efficacia e sicurezza riguardanti dabigatran e ricavati analizzando, dal database Medicare, una coorte di più di 134.000 pazienti di età superiore a 65 anni affetti da fibrillazione atriale non valvolare e naïve al trattamento con anticoagulanti orali.Graham (Office of Surveillance and Epidemiology, FDA) e collaboratori hanno pubblicato pochi giorni fa sulla rivista Circulation lo studio osservazionale di coorte riguardante il periodo compreso tra ottobre 2010 e dicembre 2012.Come sottolineava anche l’FDA nel comunicato del 15 maggio 2014, lo studio è importante non solo perché condotto su una vasta popolazione di pazienti in età avanzata, ma anche perché le metodologie utilizzate per la raccolta e l’analisi dei dati relativi agli eventi erano sofisticate e prevedevano anche la correzione per molte variabili potenzialmente confondenti.L’analisi del database Medicare, con un follow-up di 37.500 anni-persona, ha evidenziato per dabigatran rispetto a warfarin una riduzione del 20% del rischio di ictus ischemico, del 66% del rischio di emorragia intracranica e del 14% del rischio di morte. I dati riguardanti l’infarto del miocardio si avvicinano maggiormente: la riduzione del rischio, con dabigatran rispetto a warfarin è infatti pari all’8%.Unico dato in controtendenza è quello dei sanguinamenti gastrointestinali maggiori, risultato maggiore nei pazienti trattati con dabigatran rispetto a warfarin: questo incremento del rischio sembra però essere limitato alle donne con 75 anni o più e agli uomini con 85 anni o più anziani.

Incidence rate per 1000 person-years Medicare analysis: results Incidence rate per 1000 person-years Adjusted HR (95% CI) Dabigatran Warfarin Ischaemic stroke 11.3 13.9 0.80 (0.67-0.96) Intracranial haemorrhage 3.3 9.6 0.34 (0.26-0.46) Major gastrointestinal bleeding 34.2 26.5 1.28 (1.14-1.44) Acute myocardial infarction 15.7 16.9 0.92 (0.78-1.08) Mortality 32.6 37.8 0.86 (0.77-0.96) Dabigatran was associated with a lower risk of ischaemic stroke, intracranial haemorrhage and death than warfarin. Risk of MI was similar for dabigatran and warfarin. Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg together without stratification by dose. Warfarin is the reference group. CI = confidence interval; HR = hazard ratio; MI = myocardial infarction; Available at: www.fda.gov/Drugs/DrugSafety/ucm396470.htm (accessed May 2014)

Incidence rate per 1000 person-years Medicare analysis: results Incidence rate per 1000 person-years Adjusted HR (95% CI) Dabigatran Warfarin Ischaemic stroke 11.3 13.9 0.80 (0.67-0.96) Intracranial haemorrhage 3.3 9.6 0.34 (0.26-0.46) Major gastrointestinal bleeding 34.2 26.5 1.28 (1.14-1.44) Acute myocardial infarction 15.7 16.9 0.92 (0.78-1.08) Mortality 32.6 37.8 0.86 (0.77-0.96) Dabigatran was associated with a lower risk of ischaemic stroke, intracranial haemorrhage and death than warfarin. Risk of MI was similar for dabigatran and warfarin. Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg together without stratification by dose. Warfarin is the reference group. CI = confidence interval; HR = hazard ratio; MI = myocardial infarction; Available at: www.fda.gov/Drugs/DrugSafety/ucm396470.htm (accessed May 2014)

Incidence rate per 1000 person-years Medicare analysis: results Incidence rate per 1000 person-years Adjusted HR (95% CI) Dabigatran Warfarin Ischaemic stroke 11.3 13.9 0.80 (0.67-0.96) Intracranial haemorrhage 3.3 9.6 0.34 (0.26-0.46) Major gastrointestinal bleeding 34.2 26.5 1.28 (1.14-1.44) Acute myocardial infarction 15.7 16.9 0.92 (0.78-1.08) Mortality 32.6 37.8 0.86 (0.77-0.96) Dabigatran was associated with a lower risk of ischaemic stroke, intracranial haemorrhage and death than warfarin. Risk of MI was similar for dabigatran and warfarin. Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg together without stratification by dose. Warfarin is the reference group. CI = confidence interval; HR = hazard ratio; MI = myocardial infarction; Available at: www.fda.gov/Drugs/DrugSafety/ucm396470.htm (accessed May 2014)

Incidence rate per 1000 person-years Medicare analysis: results Incidence rate per 1000 person-years Adjusted HR (95% CI) Dabigatran Warfarin Ischaemic stroke 11.3 13.9 0.80 (0.67-0.96) Intracranial haemorrhage 3.3 9.6 0.34 (0.26-0.46) Major gastrointestinal bleeding 34.2 26.5 1.28 (1.14-1.44) Acute myocardial infarction 15.7 16.9 0.92 (0.78-1.08) Mortality 32.6 37.8 0.86 (0.77-0.96) Dabigatran was associated with a lower risk of ischaemic stroke, intracranial haemorrhage and death than warfarin. Risk of MI was similar for dabigatran and warfarin. Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg together without stratification by dose. Warfarin is the reference group. CI = confidence interval; HR = hazard ratio; MI = myocardial infarction; Available at: www.fda.gov/Drugs/DrugSafety/ucm396470.htm (accessed May 2014)

Global Registry on Long-Term Oral Global Registry on Long-Term Oral Antithrombotic Treatment in AF Patients Collection of data on dabigatran in countries/regions and globally Increase knowledge on AF patients, treatment patterns, and outcome events in a real-world setting Involvement of up to 2200 physicians worldwide: GPs, cardiologists, neurologists, internists, geriatricians, etc – hospital based or private practice up to 56 000 patients 2200 sites up to 50 countries

In totale 6700 pt

Comparison of Main Outcomes: XANTUS versus ROCKET AF CHADS2 Prior stroke# ROCKET AF1 3.5 55% XANTUS2 2.0 19% #Includes prior stroke, SE or TIA; *Events per 100 patient-years Patel MR et al, N Engl J Med 2011;365:883–891; 2. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466

Major Bleeding Rates with Rivaroxaban: Low and consistent in clinical trial and real life setting Data on more than 54.000 rivaroxaban treated patients ROCKET AF1 mean CHADS2-Score 3.5 Dresden NOAC Registry2 mean CHADS2-Score 2.4# US DoD PMSS3 mean CHADS2-Score 2.25 XANTUS4 mean CHADS2-Score 2.1 n=7,111 n=1,200 n=39,052 n=6,784 3,6 2.9 Event rate (%/year) 3.1 2.9 2.1 *Major bleeding definitions according to ISTH; # modified ISTH definition (additionally included surgical revision from bleeding) **Major bleeding was defined by the Cunningham algorithm3 #55th ASH Meeting 2013, Oral presentation, Abstract 213, https://ash.confex.com/ash/2013/webprogram/Paper58333.html 1. Patel MR et al. N Engl J Med 2011; 365(10):883–891; 2. Beyer—Westendorf et al. Blood 2014;124(6); 955-962; 3. Peacok ESC 2015; 4. Camm et al Eur Heart J 2015; 5. Tamayo et al. Clin Cardiol 2015

Conclusions The efficacy and major bleeding results of NOA vs. warfarin were consistent NOA have benefits over warfarin that are maintained irrespective of age NOA have benefits over warfarin that are maintained irrespective of renal function NOA real world data are consistent

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