1. Gli anticoagulanti diretti nel mondo reale
Il neurologo: Efficacia e sicurezza
Antonio Carolei* e Cindy Tiseo Clinica Neurologica e Stroke Unit Avezzano - Sulmona
Università degli Studi dell’Aquila
*Presidente Italian Stroke Organization
Roma, 15 febbraio 2016

2. Natural history of AF 2

3. J Am Heart Assoc 2016;5:e002984 doi: 10.1161/JAHA.115.002984
Implementation of an emergency department observation unit AF algorithm was associated with signifi cantly
decreased hospital admissions without increasing the rates of return emergency department visits, hospitalization, or adverse
events within 30 days 3

4. …despite a great unmet need for safer antiarrhythmic drugs, developments in this field are expected to be much slower
Two potential antiarrhythmic drugs are forecast to enter the market within the next decade. Both drugs candidates are expected to launch late in the forecast period and will not reach peak sales until after 2023
The low level of activity in the pipeline is expected to continue due to the high risk involved in developing antiarrhythmic drugs 4

5. VKAs vs NOACs 5

6. Decision tree for antithrombotic therapy
in patients with nvAF
Aspirina si 6

7. Antithrombotic therapy
Eur Heart J 2012;33: & Europace 2015;17:
Aspirina no

8. Why should we care about any real world data versus clinical trial?
Efficacy (Clinical trial data)
Does it work under ideal
circumstances?
Controlled clinical trial
environment
Geared to get FDA approval
Fixed regimen with highly
motivated patients
Compliance usually high
External validity - low to medium
Effectiveness (Real-world data)
Does it work under usual
circumstances?
Real world clinical practice
Drug performance in the real
world
Flexible regimen with your regular
day to day clinic patient
Low to high compliance
External validity - medium to high
La validità interna di una ricerca risponde al quesito: i risultati trovati rispecchiano effettivamente il fenomeno studiato o dipendono da altre variabili non considerate.
La validità esterna di una ricerca fa riferimento alla possibilità di generalizzare, cioè di estendere le conclusioni tratte dalla ricerca empirica ad ambiti più ampi rispetto a quello in cui la ricerca è stata compiuta. 8

9. Favourable risk-benefit profile
Lancet 2014;383:

10. Efficacy of NOAC in the SPAF Trials
Ischemic stroke or Systemic embolism
RRR 19%
Major bleeding
RRR 14% *
Lancet 2014;383:

11. Efficacy of NOAC in the SPAF Trials
Secondary efficacy and safety outcomes
Ischemic vs hemorrhagic stroke
RRR 8% *
RRR 51%
RRR 52% *
Lancet 2014;383:

12. Stroke or SE Major bleeding
Compared with standard adjusted dose VKA, new oral anticoagulants were associated with modest reductions in the absolute risk of stroke and major bleeding.
OR for all-cause stroke or systemic embolism (A) and major bleeding (B) in Bayesian network meta-analysis versus standard adjusted dose VKA. CrI, credible interval; VKA, vitamin K antagonist. BMJ Open 2014;4:e004301
Compared with standard adjusted dose VKA, new oral anticoagulants were associated with modest reductions in the absolute risk of stroke and major bleeding.
Bayesian intervals (credible intervals) treat their bounds as fixed and the estimated parameter as a random variable, whereas frequentist confidence intervals treat their bounds as random variables and the parameter as a fixed value.
Major bleeding

13. What do these meta-analyses tell us?
Overall the results appear reassuring for the NOACs
NOACs are associated with significant reduction in major bleeding, fatal bleeding, intracranial bleeding, clinically relevant non-major bleeding and total bleeding
However, results should be interpreted in the context that these analyses included patients that participated in major randomized trials where the environment was more controlled
They may not reflect the “true” incidence of bleeding in the real day to day clinical practice world

15. The EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot Registry has provided systematic collection of contemporary data regarding the management and treatment of AF by cardiologists in ESC member countries
Oral anticoagulant use has increased, but novel OAC use was still low (8%). Compliance with the treatment guidelines for patients with the lowest and higher stroke risk scores remains suboptimal
Europace 2014:16,

16. Between February 2012 and March 2013
Europace 2014:16,

17. *
J Am Coll Cardiol 2013 ;61:

18. MARKETSCAN REAL-WORLD Incidenza dell’evento (%/anno)
Major bleedings
Warfarin vs Apixaban
3.09
2.13
Studio ARISTOTLE
HR=0.69 (95% CI: 0.60–0.80)
RRR 31%
N=9052
N=9088
MARKETSCAN REAL-WORLD
HR=0.52 (95% CI: 0.30–0.89)
RRR 48%
4.66
Incidenza dell’evento (%/anno)
2.35
N=12,713
N=2402
Real World Comparison Of Major Bleeding Risk Among Non-valvular Atrial Fibrillation Patients Newly Initiated On Apixaban, Dabigatran, Rivaroxaban Or Warfarin
Lip GYH, Pan X, Kamble S, Kawabata H, Mardekian J, Masseria C, Bruno A, Phatak H
N Engl J Med 2011;365: & Lip ESC 2015

19. Warfarin vs Apixaban - Rivaroxaban - Dabigatran
Major bleedings
Warfarin vs Apixaban - Rivaroxaban - Dabigatran
RRR 48%
RRR 12%
I risultati sono stati aggiustati sulla base delle caratteristiche basali della popolazione.
I dati mostrano che rispetto ai pazienti che hanno iniziato il trattamento con warfarin, i pazienti che hanno iniziato apixaban avevano meno probabilità di avere un evento di sanguinamento maggiore. Non c’erano differenze significative nell’incidenza di sanguinamenti maggiori tra i pazienti che hanno iniziato warfarin e quelli che hanno iniziato rivaroxaban o dabigatran.
Dopo aggiustamento per le caratteristiche basali, rispetto ai pazienti che hanno iniziato apixaban 5mg, quelli che hanno iniziato warfarin (HR: 1.90, 95% CI: 1.03 – 3.51, P=0.0399) o rivaroxaban 20mg (HR: 2.06, 95% CI: 1.11 – 3.84, P=0.0226) avevano una probabilità significativamente maggiore di avere un sanguinamento maggiore.
I pazienti che hanno iniziato dabigatran 150mg (HR: 1.56, 95% CI: 0.79 – 3.04, P=0.1977) avevano un numero maggiore ma non significativo di sanguinamenti maggiori rispetto a quelli che hanno iniziato apixaban.
Tra i pazienti con FANV che iniziano una terapia AC in un contesto real world, l’inizio della terapia con rivaroxaban o warfarin è associato ad un rischio significativamente maggiore di sanguinamenti maggiori rispetto all’inizio della terapia con apixaban.
Tra i pazienti con FANV che iniziano una terapia AC in un contesto real world, rispetto ai pazienti che hanno iniziato la terapia con warfarin (standard of care), quelli che hanno iniziato apixaban avevano una probabilità significativamente inferiore di avere un sanguinamento maggiore.
Lip ESC 2015

20. XANTUS vs ROCKET-AF
Eur Heart J 2015 [Epub ahead of print]

21. Major bleedings * Adjusted HR Favours Apixaban Favours comparator
Comparison of Major Bleeding, Stroke and Associated Medical Costs among Treatment-naïve Non-valvular Atrial Fibrillation Patients Initiating Apixaban, Dabigatran, Rivaroxaban or Warfarin within One Year of Treatment Initiation
Adjusted HR: 0.87; 95% CI: 0.74 – 1.03
P = 0.109
Adjusted HR: 0.71, RRR 29%; 95% CI: 0.62– 0.82
P < 0.001
Adjusted HR: 0.71, RRR 29%; 95% CI: 0.62 – 0.80
Favours Apixaban Favours comparator
Adjusted HR
*ARISTOTLE: HR=0.69 (95% CI 0.60–0.80)
RRR 31%, P< for superiority
Major bleedings *

22. Stroke and SE * * Adjusted HR Favours Apixaban Favours comparator
Comparison of Major Bleeding, Stroke and Associated Medical Costs among Treatment-naïve Non-valvular Atrial Fibrillation Patients Initiating Apixaban, Dabigatran, Rivaroxaban or Warfarin within One Year of Treatment Initiation
*ARISTOTLE: HR 0.79 (95% CI: )
RRR 21%, P=0.01 for superiority
Stroke and SE
Adjusted HR: 0.91; 95% CI: 0.81 – 1.02
P = 0.120
Adjusted HR: 0.94; 95% CI: 0.86 – 1.04
P = 0.215 *
Adjusted HR: 0.74, RRR 26%; 95% CI: 0.68 – 0.81
P <0.001 *
Favours Apixaban Favours comparator
Adjusted HR

23. Circ Cardiovasc Qual Outcomes 2016;DOI: 10. 1161/CIRCOUTCOMES. 115
In real-world clinical practice, dabigatran is comparable with warfarin in preventing ischemic stroke among patients with nonvalvular atrial fibrillation. However, dabigatran is associated with a lower risk for intracranial bleeding relative to warfarin, but—particularly among the elderly—a greater risk for gastrointestinal bleeding. Bleeding outcomes
from observational studies are consistent with those from the pivotal study.

24. Circ Cardiovasc Qual Outcomes 2016;DOI: 10. 1161/CIRCOUTCOMES. 115
In real-world clinical practice, dabigatran is comparable with warfarin in preventing ischemic stroke among patients with nonvalvular atrial fibrillation. However, dabigatran is associated with a lower risk for intracranial bleeding relative to warfarin, but—particularly among the elderly—a greater risk for gastrointestinal bleeding. Bleeding outcomes
from observational studies are consistent with those from the pivotal study.

25. Conclusions Registries and trials are complementary
Randomized clinical trials determine the efficacy and safety compared with VKA
Registries test how these drugs work in the real world
Some patients are overtreated and do not need anticoagulation (patients at very low risk for stroke)
Other patients at high risk for stroke do not receive the treatment they need

26. THANKS!