This document summarizes data from clinical studies and real-world evidence on the new oral anticoagulants for atrial fibrillation. It finds that dabigatran 150mg twice daily reduces ischemic stroke and mortality compared to warfarin based on a study of 56,576 Medicare patients, but increases gastrointestinal bleeding in those over 75 years old. Real-world data also finds apixaban reduces major bleeding, hospitalizations and inpatient bleeding compared to dabigatran and rivaroxaban. Studies of patients over 75 years old initiating anticoagulants find warfarin, rivaroxaban and dabigatran have higher risks of major bleeding than apixaban. The document

1. Actualización de los nuevos anticoagulantes orales
en base a datos en práctica clínica real
Madrid, septiembre 2016
Domingo Marzal Martín
ANTICOAGULACIÓN 3.0

2. AVK …“nuevo ACO”
datos de vida real

3. Bleeding
Thrombosis
Björck F, et al. JAMA Cardiol. 2016;1:172-80

4. Bleeding
CNS Bleeding
Björck F, et al. JAMA Cardiol. 2016;1:172-80

5. stroke or SEE secondary efficacy outcomes
major bleedings secondary safety outcomes
Ruff CT, et al. Lancet 2014;383:955-62
Efficacy and safety of NOACs vs warfarin in atrial fibrillation: a meta-analysis of randomised trials

6. dabigatran
datos de vida real

7. Connolly et al. N Engl J Med. 2009;361:1139-51
Graham DJ et al. Circulation. 2015;131:157-64
Independent FDA study of Medicare patients

8. Resultados dabigatran 150 mg BID
n=56.576
Medicare analysis1
HR (95% CI)
Ictus isquémico 0.70 (0.57–0.85)
Mortalidad 0.76 (0.67–0.86)
Hemorragia grave GI 1.51 (1.32–1.73)
HIC 0.30 (0.21–0.42)
Favor warfarina
0.1 2.01.0
Favor dabigatran
Dabigatran vs warfarina
Hemorragia grave GI superior en:
•Mujeres ≥ 75 años
•Hombres ≥ 85 años
Graham DJ et al. Circulation. 2015;131:157-64

9. Connolly et al. N Engl J Med. 2009;361:1139-51
Villines TC, et al. Thromb Haemost. 2015;14:1290-8
Department of Defense

10. Larsen TB et al. Am J Med. 2014;127:650-6
National Danish Registries
bleeding risk
n=11.315
0.10 0.50 1.00 2.00 5.00
0.72 (0.59–0.88)
0.93 (0.74–1.16)
0.52 (0.28–0.95)
0.50 (0.27–0.94)
0.30 (0.17–0.54)
Favours dabigatran Favours warfarin
VKA-naïve stratum
0.68 (0.55–0.84)
0.67 (0.53–0.85)
0.70 (0.33–1.52)
1.45 (0.84–2.50)
0.33 (0.17–0.66)
Any
Major
Fatal
GI
ICH
Any
Major
Fatal
GI
ICH
Dabigatran 110 mg
vs warfarin
Dabigatran 150 mg
vs warfarin
HR (95% CI)

11. rivaroxaban
datos de vida real

12. Patel MR, et al. N Engl J Med. 2011;365:883-91 Tamayo S, et al. Clin Cardiol. 2015;38:63-8
0
1
2
3
4
Hemorragias mayores
3,6%
2.9%
ROCKET AF
Farmacovigilancia
Eventos(%/año)
n=7.111
rivaroxaban
n=27.476
US Pharmacovigilance Study

13. US Pharmacovigilance Study
0
0,2
0,4
0,6
Hemorragia
intracraneal
Hemorragia mortal
0,5%
0,2%0,2%
<0,1%
ROCKET AF
Farmacovigilancia
Eventos(%/año)
Patel MR, et al. N Engl J Med. 2011;365:883-91 Tamayo S, et al. Clin Cardiol. 2015;38:63-8

14. CHADS2 Ictus previoa
ROCKET AF 3,5 55 %
XANTUS 2,0 19 %
0
0,5
1
1,5
2
Ictus/ES Todos tipos ictus Muerte
1,7 1,7
1,9
0,8 0,7
1,9
ROCKET AF XANTUS
Tasadeincidencia,%/año
Camm AJ, et al, Eur Heart J. 2016;37:1145-53

15. CHADS2 Ictus previoa
ROCKET AF 3,5 55 %
XANTUS 2,0 19 %
0
0,5
1
1,5
2
2,5
3
3,5
4
Hemorragia
mayor
HIC Hemorragia
digestiva
3,6
0,5
2,02,1
0,4
0,9
ROCKET AF XANTUS
Tasadeincidencia,%/año
Camm AJ, et al, Eur Heart J. 2016;37:1145-53

16. apixaban
datos de vida real

17. baseline characteristics
Deitelzweig S, et al. ESC Congress 2015; oral poster no.1971

18. Deitelzweig S, et al. ESC Congress 2015; oral poster no.1971
major bleeding
all-cause hospitalization

19. ***P<.001; **P<.01; *P<.05
Tepper P; et al. ESC Congress 2015; oral poster no.1975

20. Tepper P; et al. ESC Congress 2015; oral poster no.1975
Dabigatran vs apixaban
0 0,5 1 1,5 2 0 0,5 1 1,5 2 2,5
Hemorragia grave
HIC
Hemorragia GI
grave
Hemorragia NGCR
Hemorragia
GI NGCR
CRI CRI
Favorece a dabigatrán Favorece a apixaban Favorece a rivaroxaban Favorece a apixaban
CRI 1.34 (1.20-1.51)CRI 0.99 (0.86-1.12)
CRI 1.41 (1.01-1.97)CRI 1.08 (0.75-1.55)
CRI 1.54 (1.23-1.91)CRI 1.04 (0.83-1.32)
CRI 1.39 (1.28-1.51)CRI 1.03 (0.95-1.12)
CRI 1.50 (1.31-1.73)CRI 1.24 (1.07-1.44)
Rivaroxaban vs apixaban

21. Tepper P; et al. ESC Congress 2015; oral poster no.1975
adjusted incidences of bleeding
inpatient bleeding

22. 0%
2%
4%
6%
8%
10%
12%
14%
16%
18%
20%
0 30 60 90 120 150 180
CumulativeProportionofPatients
withAnyBleed
Days following Index
Apixaban
Dabigatran
Warfarin
Rivaroxaban
Log rank P < 0.0001
Lin I, et al. ESC Congress 2015; oral poster no.P6215
Real-world Bleeding Risk among NVAF Patients Prescribed Apixaban, Dabigatran,
Rivaroxaban, and Warfarin: Analysis of Electronic Health Records
analysis of any bleed during follow up
Warfarina vs apixaban: HR 1.34 (95% Cl 1.13–1.58)
Rivaroxaban vs apixaban: HR 1.46 (95% Cl 1.23–1.75)
Dabigatrán vs apixaban: HR 0.91 (95% Cl 0.73–1.13)

23. Lip G, et al. ESC Congress 2015; oral poster no.P6217
Real World Comparison of Major Bleeding Risk Among NVAF Patients
Newly Initiated on Apixaban, Dabigatran, Rivaroxaban or Warfarin
Dabigatran (4.173)
150 mg NR
3.768 405
Rivaroxaban (10.050)
20 mg NR
8.066 1.984
Apixaban (2.402)
5 mg NR
2.057 345
Warfarin (12.713)
cumulative incidence of major bleeding
%patientsmajorbleeding
(Inpatientbleeding)
Time from Anticoagulation initiation (days)
0
0
1
2
3
4
5
30 60 90 120 150 180 210 240 270 300 330 360 390
Warfarin vs Apixaban: HR 1.93 (95% CI 1.12–3.33) P=0.018
Rivaroxaban vs Apixaban: HR 2.19 (95% Cl 1.26 –3.79) P=0.0052
Dabigatran vs Apixaban: HR 1.71 (95% Cl 0.94–3.10) P= 0.079

24. Lip G, et al. ESC Congress 2016 Poster Presentation
Is Major Bleeding Risk for Oral Anticoagulants Similar Between Non-Valvular Atrial Fibrillation
Patients Newly Initiated On Warfarin and Propensity Score Matched NOAC Initiators? A Real-
World Study

25. Lip G, et al. ESC Congress 2016 Poster Presentation
Is Major Bleeding Risk for Oral Anticoagulants Similar Between Non-Valvular Atrial Fibrillation
Patients Newly Initiated On Warfarin and Propensity Score Matched NOAC Initiators? A Real-
World Study

26. Larsen TB et al. BMJ 2016;353:i3189

27. Masseria LI, et al. ESC Congress 2016 Presentation

28. Lip G, et al. ESC Congress 2016 Poster Presentation
Major Bleeding Risk in Patients ≥75 Years with NVAF Initiating Oral Anticoagulants:
A Real-world Comparison of Warfarin, Apixaban, Dabigatran, or Rivaroxaban

30. anticoagulación 3.0
idarucizumab

32. Adapted from Lane et al. Presented at ESOC 2016 (ESOC6-0603)

35. gracias por vuestra atención
domingo.marzal@secardiologia.es
@domingomarzal