1. 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

2. 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?

3. 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

4. Lancet, published online December 4, 2013

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

6. MAJOR BLEEDING
Ruff CT, Lancet, December 4, 2013

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

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

9. 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 May; 108(5):
The role of tissue factor and factor VIIa in hemostasis.

10. Antidoto

11. 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

12. NOA in Elderly patients

19. 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

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

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

22. NOA in patients with renal insufficiency

23. 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

24. 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.

25. Xa inhibitors are eliminated from the body
via multiple routes

26. 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:

27. 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:

28. Raccomandazioni dell’ESC nei pazienti con IR

29. Raccomandazioni dell’EHRA nei pazienti con IR (2015)

30. 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< 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

31. Backgroun: Vitamin K-Antagonists Induce Vascular Damage
Price et al, Arterioscler Thromb Vasc Biol 18 (1998):
Schurgers et al, Blood 109 (2007):
Brodsky et al, Kidney Int 109 (2011):
Krüger et al, Arterioscler Thromb Vasc Biol 33 (2013):

32. NOA in patients with valvular atrial fibrillation

33. 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

34. NAO in numeri…. 180000 pz nei trials
6200 articoli - studi clinici (PUBMED)
Almeno 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

35. Real world data

36. 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

37. 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 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 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.

38. 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 ( )
Intracranial haemorrhage
3.3
9.6
0.34 ( )
Major gastrointestinal bleeding
34.2
26.5
1.28 ( )
Acute myocardial infarction
15.7
16.9
0.92 ( )
Mortality
32.6
37.8
0.86 ( )
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: (accessed May 2014)

39. 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 ( )
Intracranial haemorrhage
3.3
9.6
0.34 ( )
Major gastrointestinal bleeding
34.2
26.5
1.28 ( )
Acute myocardial infarction
15.7
16.9
0.92 ( )
Mortality
32.6
37.8
0.86 ( )
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: (accessed May 2014)

40. 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 ( )
Intracranial haemorrhage
3.3
9.6
0.34 ( )
Major gastrointestinal bleeding
34.2
26.5
1.28 ( )
Acute myocardial infarction
15.7
16.9
0.92 ( )
Mortality
32.6
37.8
0.86 ( )
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: (accessed May 2014)

41. 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 ( )
Intracranial haemorrhage
3.3
9.6
0.34 ( )
Major gastrointestinal bleeding
34.2
26.5
1.28 ( )
Acute myocardial infarction
15.7
16.9
0.92 ( )
Mortality
32.6
37.8
0.86 ( )
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: (accessed May 2014)

42. 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
patients
2200 sites
up to 50 countries

43. In totale 6700 pt

44. 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: /eurheartj/ehv466

45. Major Bleeding Rates with Rivaroxaban:
Low and consistent in clinical trial and real life setting
Data on more than 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,
1. Patel MR et al. N Engl J Med 2011; 365(10):883–891; 2. Beyer—Westendorf et al. Blood 2014;124(6); ; 3. Peacok ESC 2015; 4. Camm et al Eur Heart J 2015; 5. Tamayo et al. Clin Cardiol 2015

46. 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

47. GRAZIE PER L’ATTENZIONE