1. Fibrillazione atriale:
dall’Epidemiologia alle nuove terapie
Roma, 16 Marzo 2013
Vecchi e nuovi anticoagulanti orali a confronto
Giuseppe Patti
Università Campus Bio-Medico di Roma

2. Why a novel anti-thrombotic Rx is needed in AF pts?
 No stroke protection with aspirin (with or without clopidogrel)
 Warfarin effective for stroke prevention, but
- Delayed onset/offset
- Unpredictable dose response
- Narrow therapeutic index
- Drug-drug, drug-food interactions
- Problematic monitoring and compliance
- High bleeding (especially ICH)
- Slow reversibility

4. New Anticoagulants
Xa factor inhibitor:
Rivaroxaban
Apixaban
Edoxaban

5. New anticoagulants:
advantages
 Short half-life:
- Immediate onset of action
- no need for bridging
 Fixed doses
 No lab. monitoring
 A few drug-drug interactions (no food interactions)

6. New oral anticoagulants: how do they compare?
Dabigatran Rivaroxaban Apixaban Edoxaban
Action Anti-IIa Anti-Xa Anti-Xa Anti-Xa
Prodrug Yes (esterases) No No No
Bioavailability (%) 6 80-100 50-66 50
Half-life (hrs) 14-17 7-11 8-15 9-11
Protein binding (%) 35 95 87 50
Onset to peak 2-3 2-4 3 1-1.5
action (hrs)
Metabolism 80% renal CYP 3A4 CYP 3A4 CYP 3A4
20% glucur. 33% renal 22% renal 23% renal
Dose 110/150 mg BID 20 mg qD 5 mg BID 30-60 mg qD
Drug interaction P-glycoprotein CYP 3A4 CYP 3A4 CYP 3A4
P-glycoprotein P-glycoprotein P-glycoprotein

7. Questions and answers on the use of dabigatran and perpectives on the use of
other new oral anticoagulants in patients with atrial fibrillation
Pengo V., Thrombosis and Haemostasis 2011
Predictable drug interactions of the new oral anticoagulants according to the type of metabolism.

8. New oral anticoagulants: trials’ characteristics
RELY ROCKET-AF ARISTOTLE
(N=18,113) (N=14,264) (N=18,201)
Age (yrs, mean) 72 73 70
Female (%) 36 40 35
Prior stroke/TIA (%) 20 55 19
Diabetes (%) 23 40 25
Prior CHF (%) 32 62 35
VKA naive (%) 50 38 43
CHADS2 > 3 (%) 32 87 30
CHADS2 (mean) 2.1 3.5 2.1
TRR (%) 64 58 62

9. RELY trial – Primary outcome
Stroke or Systemic Embolism
1.53%/yr vs 1.69%/yr
0.91 (0.74-1.11)
1.11%/yr vs 1.69%/yr
0.66 (0.53-0.82)
Connolly SJ et al. NEJM 2009

10. RELY trial – Safety outcome
P=0.31
P=0.003
4,0
3,5 3,36
3,11
Event rate per year (%)
3,0 2,71
2,5
Warfarin
2,0
Dabigatran 110 mg
1,5 Dabigatran 150 mg
1,0
0,5
0,0
Major bleeding
Connolly SJ et al. NEJM 2009

11. ROCKET-AF trial
Primary Efficacy Outcome: Stroke and systemic embolism
Rivaroxaban Warfarin
Event Event HR
P-value
Rate Rate (95% CI)
On 0.79
Treatment 1.70 2.15 0.015
(0.65,0.95)
N= 14,143
ITT 0.88
2.12 2.42 0.117
N= 14,171 (0.75,1.03)
Rivaroxaban Warfarin
better better
Patel MR et al. NEJM 2011

12. ROCKET-AF trial: Safety outcome
Rivaroxaban Warfarin
HR
Event Rate Event Rate P-value
(95% CI)
Major and non-major Clinically
14.91 14.52 1.03 (0.96, 1.11) 0.442
Relevant
Cumulative event rate (%)
Patel MR et al. NEJM 2011

13. ARISTOTLE trial: primary efficacy outcome
HR 0.79
1.60%/yr
(95% CI, 0.66-0.95);
P=0.011) 1.27%/yr
Granger CB et al. NEJM 2011

14. ARISTOTLE trial: Safety outcome
3.09%/yr
HR 0.69
(95% CI, 0.60-0.80);
P<0.001
2.13%/yr
Granger CB et al. NEJM 2011

15. New oral anticoagulants: main trials’ results
Dabigatran Dabigatran Rivaroxaban Apixaban
150 mg 110 mg (N=14,264) (N=18,201)
(N=18,113) (N=18,113)
Stroke/embol. ↓ = ↓* ↓
Ischemic stroke ↓ = = =
Major bleed = ↓ = ↓
Fatal bleed ↓ ↓ ↓ ↓
(life threath.)
IC bleed ↓ ↓ ↓ ↓
Minor bleed ↓ ↓ = =
GI bleed ↑ = ↑ =
Death ↓ (P=0.05) = = ↓

16. NOACS: primary efficacy & safety outcome
ESC Working Group on Thrombosis: Task Force on anticoagulants in heart disease position paper
MT
De Caterina R. JACC 2012;59:1413

17. Ischemic Stroke
ITT : p-value
Dabigatran 110 mg 149 1.34% / yr 1.20 0.35
Dabigatran 150 mg 111 0.92% / yr 0.76 0.03
Warfarin 142 1.20% / yr RELY
Rivaroxaban 20 mg 149 1.62% / yr 0.99 0.92*
Warfarin 161 1.64% / yr
ROCKET-AF
Apixaban 5 mg 162 0.97% / yr 0.92 0.42
Warfarin 175 1.05% / yr
ARISTOTLE
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011

18. AGE AND RENAL FUNCTION SUBGROUP ANALYSIS:
STROKE AND NON-CNS EMBOLISM
Annual rate (%)
D 110 D 150 D 110 mg BID D 150 mg BID
Warfarin vs. warfarin vs. warfarin
mg BID mg BID
Age (yrs) P=0.76 P=0.072
<65 1.48 0.69 1.35
65–74 1.26 0.98 1.43
≥75 1.87 1.43 2.1
Creatinine clearance (mL/min) P=0.58 P=0.036
30–50 2.26 1.33 2.65
51–80 1.65 1.24 1.76
>80 0.92 0.72 1
0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0
Dabigatran Warfarin Dabigatran Warfarin
better better better better
BID = twice daily; CNS = central nervous system; D = dabigatran; P values for interaction.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Healey JS, et al. ACC 2010; abstr 1078-120.

19. AGE AND RENAL FUNCTION SUBGROUP
ANALYSIS: MAJOR BLEEDING
Annual rate (%)
D 110 D 150 D 110 mg BID D 150 mg BID
Warfarin vs. warfarin vs. warfarin
mg BID mg BID
Age (yrs) P=0.0003 P=0.0001
<65 0.76 0.79 2.32
65–74 2.12 2.45 3.08
≥75 4.21 4.81 4.09
Creatinine clearance (mL/min) P=0.1 P=0.091
30–50 5.07 4.85 5.17
51–80 2.62 3.04 3.44
>80 1.36 1.88 2.18
0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0
Dabigatran Warfarin Dabigatran Warfarin
better better better better
BID = twice daily; D = dabigatran; P values for interaction.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Healey JS, et al. ACC 2010; abstr 1078-120.

20. New anticoagulants and CRF
 Longer half-life
 Monitoring of renal function
 Doses reduction?
Connolly SJ et al, NEJM 2009

21. New oral anticoagulants in pts receiving anti-PLT Rx
Triple therapy and major bleeding in RE-LY
Warfarin Dabigatran Dabigatran RR (95% RR (95%
(%) 110 mg BID 150 mg BID CI) CI)
(%) (%) Dabigatran Dabigatran
110 mg BID 150 mg BID
vs warfarin vs warfarin
ASA + 5.2 4.7 4.7 0.77 0.81
clopidogrel (0.50-1.21) (0.52-1.26)
No ASA + 3.5 2.8 3.2 0.81 0.95
clopidogrel (0.61-0.94) (0.82-1.10)
Connolly SJ et al. N Engl J Med 2009

22. New anticoagulants and
risk of CV events
MI or ACS
 Issues regarding control population  Stroke prevention independent of CAD
 Lower protection than warfarin  Ximelagatran reduced CV risk
 Studies not powered for MI  No dose-dependent effect
 Data not corrected for beta-block., statins  No correlation between CV risk and OR for MI
Uchino K et al. Arch Intern Med 2012 Hohnloser SH et al. Circulation 2012

23. Reduced LOS with dabigatran
End point Standard Dabigatran, n=18 p
anticoagulation,
n=18
Duration of in- 4.0 2.0 <0.001
hospital
anticoagulation
(median days)
Hospital length of 86 60.4 <0.05
stay (mean hours)
Hospital length of 75.5 49.4 <0.01
stay (median hours)
David A Vorchheimer, ACC Congress 2013

24. NAO e Cardioversione: raccomandazioni
Nei pazienti con FA in corso da ≥48 ore o quando la durata di FA è
sconosciuta, la terapia anticoagulante orale (es. AVK con INR 2-3 o I B
Dabigatran) è raccomandata per ≥3 settimane prima e per ≥4
settimane dopo cardioversione, indipendentemente dalla tipologia
(elettrica o farmacologica orale/endovenosa)
Non ci sono dati pubblicati relativi alla cardioversione
con Rivaroxaban o Apixaban

25. Practical issues with
new anticoagulants
 Is bridging Rx needed?
 Stop before surgery
 Switching from warfarin
 Switching from LMWH
 Switching from UFH

26. How to manage a bleeding event
while on Rx with new anticoagulants?
 Discontinue the anticoagulant
 Investigate and treat the source of bleeding
 Maintain diuresis
 Blood volume replacement with/without fresh-frozen plasma
 Prothrombin complex concentrates, recombinant factor VIIa
 Platelet concentrates in case of Rx with long-acting
antiplatelet drugs
 Use of activated charcoal Rx
 Dialysis for dabigatran

27. New anticoagulants Warfarin
 Economic issues  Excellent efficacy
 Unresolved issues  Low cost
- No standardized monitoring  Long track record
- Adherence to Rx  Centralized anticoag. clin.
- Lack of antidote  Point of care testing
- Long-term safety (real world)
- No head-to-head comparison
 INR q 12 w if stable

28. New anticoagulants: Summary
 Superior to aspirin
 At least non-inferior to warfarin for ischemic thrombo-embolic
end-point
 Significant reduction of ICH and fatal bleed
 Consistent data according to history of previous stroke and CHADS
score, but dabigatran reduced ischemic stroke
 Possibility to choice the dabigatran dose according to bleeding risk
 Selection/prioritization of pts for these agents: pts unwilling to take
warfarin, new pts, pts with unstable INR or events while on warfarin;
pts with stable INR?
 Evaluation in other settings of pts requiring anticoagulation

30. D 110 R D 150
Anti-PLT Rx
CYP
CYP (high bleeding) (low bleeding)
High bleeding risk
Older
age CRF
GI bleed
GP drugs
Good INR
Valve prosthesis/
Other indication for OAC
A W

31. AGE AND RENAL FUNCTION SUBGROUP ANALYSIS:
STROKE AND NON-CNS EMBOLISM
Annual rate (%)
D 110 D 150 D 110 mg BID D 150 mg BID
Warfarin vs. warfarin vs. warfarin
mg BID mg BID
Age (yrs) P=0.76 P=0.072
<65 1.48 0.69 1.35
65–74 1.26 0.98 1.43
≥75 1.87 1.43 2.1
Creatinine clearance (mL/min) P=0.58 P=0.036
30–50 2.26 1.33 2.65
51–80 1.65 1.24 1.76
>80 0.92 0.72 1
0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0
Dabigatran Warfarin Dabigatran Warfarin
better better better better
BID = twice daily; CNS = central nervous system; D = dabigatran; P values for interaction.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Healey JS, et al. ACC 2010; abstr 1078-120.

32. AGE AND RENAL FUNCTION SUBGROUP
ANALYSIS: MAJOR BLEEDING
Annual rate (%)
D 110 D 150 D 110 mg BID D 150 mg BID
Warfarin vs. warfarin vs. warfarin
mg BID mg BID
Age (yrs) P=0.0003 P=0.0001
<65 0.76 0.79 2.32
65–74 2.12 2.45 3.08
≥75 4.21 4.81 4.09
Creatinine clearance (mL/min) P=0.1 P=0.091
30–50 5.07 4.85 5.17
51–80 2.62 3.04 3.44
>80 1.36 1.88 2.18
0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0
Dabigatran Warfarin Dabigatran Warfarin
better better better better
BID = twice daily; D = dabigatran; P values for interaction.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Healey JS, et al. ACC 2010; abstr 1078-120.

33. Study design
AF on Electrical
N = 21,107 Recording < 12 mo
Intended oral A/C
CHADS2 > 2
R
Low Exposure High Exposure Active Control
Strategy Strategy Warfarin
Edoxaban 30 mg QD Edoxaban 60 mg QD (INR 2.0 – 3.0)
Median duration of follow up 24-months
Primary Objective
Edoxaban: Therapeutically as good as Warfarin
1º EP = Stroke or SEE (Non inferiority Boundary HR 1.38)
2º EP = Stroke or SEE or All-Cause Mortality
Safety EPs = Major Bleeding, Hepatic Function
SEE=systemic embolic event
Ruff CT et al. Am Heart J. 2010;160:635-41

34. Other issues regarding
new anticoagulants
 Results of these drugs in pts with older age?
 Compliance?
 Need for monitoring?
 Anti-thrombotic Rx in pts with AF receiving coronary stents?

35. CTRs vs. real world observations
CRTs Real world
Age 30% 65%
CRF 20% 58%
Low body weight 30% 50%
Harper P et al. N Engl J Med 2012

36. Effects of Apixaban vs Warfarin Among Patients
Using and Not Using Aspirin in ARISTOTLE
HR ASA HR No ASA
Stroke or 0.55 0.80
embolism
Major bleeding 0.77 0.65
Hemorrhagic 0.40 0.51
stroke
Granger CB et al. N Engl J Med 2011

37. Messages from trials
according to patients age and renal function
 Reduction of the benefit on the efficacy endpoint with 150 mg Dabigatran over
the spectrum of ages. Maintained improvement on the efficacy endpoint with
150 mg Dabigatran in pts with CRF (real world?)
 Trend towards increase in major bleeding in older pts with 150 mg Dabigatran.
No reduction of bleeding in older pts and in pts with CRF with 110 mg
Dabigatran
 Consistent reduction in the efficacy endpoint with Apixaban and Rivaroxaban
over the spectrum of ages (possibly higher in older pts) and of renal function
 Monitoring of renal function?
 Dose modification? 15-30 ml/min Dabi 75 mg x 2; 30-50 ml/min Riva 15 mg;
creat. >1.5 mg/dl Api 2.5 mg x 2

38. ROCKET AF – primary efficacy endpoint
subgroup analysis
Hazard ratio and 95% CIs
Rivaroxaban Warfarin
n/N (%) n/N (%) p-value*
Overall 189/7,061 2.7 243/7,082 3.4
Sex 0.92
Male 103/4,270 2.4 136/4,283 3.2
Female 86/2,791 3.1 107/2,799 3.8
Age (years) 0.11
<75 107/3,988 2.7 119/4,005 3.0
≥75 82/3,073 2.7 124/3,077 4.0
Weight (kg) 0.78
≤70 63/2,004 3.1 78/2,008 3.9
70–≤90 92/3,022 3.0 129/3,133 4.1
>90 34/2,033 1.7 36/1,940 1.9
CrCl (ml/min) 0.72
<50 50/1,485 3.4 60/1,456 4.1
50–80 91/3,290 2.8 128/3,396 3.8
>80 47/2,278 2.1 54/2,221 2.4
*p-value for interaction 0.1 0.2 0.5 1 2 5 10
Safety population – on-treatment analysis Favours Favours
rivaroxaban warfarin
Patel MR et al, 2011

39. Apixaban vs Warfarin in ARISTOTLE
Granger NEJM 2011

40. Dabigatran Anti-Xa
Inhibition of both No effect on pre-existing
free and bound thrombin thrombin
Better stroke prevention? Lower bleeding?
NNT
Stroke Major bleed
Dabigatran 150 172 333
Dabigatran 110 625 143
Rivaroxaban 222 500
Apixaban 303 100

41. AGE AND RENAL FUNCTION SUBGROUP ANALYSIS:
STROKE AND NON-CNS EMBOLISM
Annual rate (%)
D 110 D 150 D 110 mg BID D 150 mg BID
Warfarin vs. warfarin vs. warfarin
mg BID mg BID
Age (yrs) P=0.76 P=0.072
<65 1.48 0.69 1.35
65–74 1.26 0.98 1.43
≥75 1.87 1.43 2.1
Creatinine clearance (mL/min) P=0.58 P=0.036
30–50 2.26 1.33 2.65
51–80 1.65 1.24 1.76
>80 0.92 0.72 1
0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0
Dabigatran Warfarin Dabigatran Warfarin
better better better better
BID = twice daily; CNS = central nervous system; D = dabigatran; P values for interaction.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Healey JS, et al. ACC 2010; abstr 1078-120.

42. AGE AND RENAL FUNCTION SUBGROUP
ANALYSIS: MAJOR BLEEDING
Annual rate (%)
D 110 D 150 D 110 mg BID D 150 mg BID
Warfarin vs. warfarin vs. warfarin
mg BID mg BID
Age (yrs) P=0.0003 P=0.0001
<65 0.76 0.79 2.32
65–74 2.12 2.45 3.08
≥75 4.21 4.81 4.09
Creatinine clearance (mL/min) P=0.1 P=0.091
30–50 5.07 4.85 5.17
51–80 2.62 3.04 3.44
>80 1.36 1.88 2.18
0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0
Dabigatran Warfarin Dabigatran Warfarin
better better better better
BID = twice daily; D = dabigatran; P values for interaction.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Healey JS, et al. ACC 2010; abstr 1078-120.

43. ROCKET AF – primary efficacy endpoint
subgroup analysis
Hazard ratio and 95% CIs
Rivaroxaban Warfarin
n/N (%) n/N (%) p-value*
Overall 189/7,061 2.7 243/7,082 3.4
Sex 0.92
Male 103/4,270 2.4 136/4,283 3.2
Female 86/2,791 3.1 107/2,799 3.8
Age (years) 0.11
<75 107/3,988 2.7 119/4,005 3.0
≥75 82/3,073 2.7 124/3,077 4.0
Weight (kg) 0.78
≤70 63/2,004 3.1 78/2,008 3.9
70–≤90 92/3,022 3.0 129/3,133 4.1
>90 34/2,033 1.7 36/1,940 1.9
CrCl (ml/min) 0.72
<50 50/1,485 3.4 60/1,456 4.1
50–80 91/3,290 2.8 128/3,396 3.8
>80 47/2,278 2.1 54/2,221 2.4
*p-value for interaction 0.1 0.2 0.5 1 2 5 10
Safety population – on-treatment analysis Favours Favours
rivaroxaban warfarin
Patel MR et al, 2011

44. Apixaban vs Warfarin in ARISTOTLE
Granger NEJM 2011

45. Messages from trials
according to patients age
 Consistent reduction of the efficacy endpoint with 150
mg Dabigatran over the spectrum of ages
 Trend towards reduction of major bleeding with 110 mg
Dabigatran confined to younger pts (no reduction of
bleeding in older pts); trend towards increase in bleeding
with 150 mg Dabigatran in older pts
 Consistent (and possibly higher in older pts) reduction in
the efficacy endpoint with Apixaban and Rivaroxaban

46. AGE AND RENAL FUNCTION SUBGROUP ANALYSIS:
STROKE AND NON-CNS EMBOLISM
Annual rate (%)
D 110 D 150 D 110 mg BID D 150 mg BID
Warfarin vs. warfarin vs. warfarin
mg BID mg BID
Age (yrs) P=0.76 P=0.072
<65 1.48 0.69 1.35
65–74 1.26 0.98 1.43
≥75 1.87 1.43 2.1
Creatinine clearance (mL/min) P=0.58 P=0.036
30–50 2.26 1.33 2.65
51–80 1.65 1.24 1.76
>80 0.92 0.72 1
0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0
Dabigatran Warfarin Dabigatran Warfarin
better better better better
BID = twice daily; D = dabigatran; P values for interaction.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Healey JS, et al. ACC 2010; abstr 1078-120.

47. AGE AND RENAL FUNCTION SUBGROUP
ANALYSIS: MAJOR BLEEDING
Annual rate (%)
D 110 D 150 D 110 mg BID D 150 mg BID
Warfarin vs. warfarin vs. warfarin
mg BID mg BID
Age (yrs) P=0.0003 P=0.0001
<65 0.76 0.79 2.32
65–74 2.12 2.45 3.08
≥75 4.21 4.81 4.09
Creatinine clearance (mL/min) P=0.1 P=0.091
30–50 5.07 4.85 5.17
51–80 2.62 3.04 3.44
>80 1.36 1.88 2.18
0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0
Dabigatran Warfarin Dabigatran Warfarin
better better better better
BID = twice daily; D = dabigatran; P values for interaction.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Healey JS, et al. ACC 2010; abstr 1078-120.

48. ROCKET AF – primary efficacy endpoint
subgroup analysis
Hazard ratio and 95% CIs
Rivaroxaban Warfarin
n/N (%) n/N (%) p-value*
Overall 189/7,061 2.7 243/7,082 3.4
Sex 0.92
Male 103/4,270 2.4 136/4,283 3.2
Female 86/2,791 3.1 107/2,799 3.8
Age (years) 0.11
<75 107/3,988 2.7 119/4,005 3.0
≥75 82/3,073 2.7 124/3,077 4.0
Weight (kg) 0.78
≤70 63/2,004 3.1 78/2,008 3.9
70–≤90 92/3,022 3.0 129/3,133 4.1
>90 34/2,033 1.7 36/1,940 1.9
CrCl (ml/min) 0.72
<50 50/1,485 3.4 60/1,456 4.1
50–80 91/3,290 2.8 128/3,396 3.8
>80 47/2,278 2.1 54/2,221 2.4
*p-value for interaction 0.1 0.2 0.5 1 2 5 10
Safety population – on-treatment analysis Favours Favours
rivaroxaban warfarin
Patel MR et al, 2011.

49. Apixaban and renal function
Hohonloser EHJ 2012

50. Messages from trials
according to renal function
 Consistent (and possibly higher in pts with CRF)
reduction of the efficacy endpoint with 150 mg
Dabigatran over the spectrum of renal function
 Trend towards lower reduction of major bleeding
with 110 mg Dabigatran in pts with CRF
 Consistent reduction in the efficacy endpoint with
Apixaban and Rivaroxaban over the spectrum of
renal function
 Monitoring of renal function?
 Dose modification? Dabigatran 15-30 ml/min 75 mg
x 2; Riva 30-50 ml/min 15 mg

51. CHADS2 subgroup analysis:
stroke and systemic embolism
 Effect of dabigatran 150 mg was consistent
Dabigatran 110 mg BID Dabigatran 150 mg BID
vs. warfarin vs. warfarin
Annual rate (%)
D 110 D 150 P=0.37 P=0.84
CHADS2 mg mg
core BID BID Warf.
0–1 1.06 0.65 1.08
2 1.45 0.84 1.38
3–6 2.12 1.88 2.73
0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0
Dabigatran Warfarin Dabigatran Warfarin
better better better better
BID = twice daily; D = dabigatran; P values for interaction
Oldgren J et al. Ann Int Med 2011;155:660−9

52.  History of stroke, TIA or non-CNS SE
OR
≥2* of the following:
 CHF
 Hypertension
 Age ≥75 years
 Diabetes
 Effect of Rivaroxaban was consistent

53. Apixaban vs warfarin in
ARISTOTLE
 Effect of Apixaban was consistent
Granger NEJM 2011

54. Prior stroke subgroup analysis: major clinical outcomes in
patients with or without previous stroke or TIA
Rate (% per year)
Dabigatran
110 mg 150 mg Warfarin Interaction P Interaction P
Stroke
Previous stroke or TIA 2.23 1.91 2.53
0.85 0.28
No previous stroke or TIA 1.24 0.78 1.34
chaemic or unknown stroke
Previous stroke or TIA 2.19 1.75 1.75
0.46 0.12
No previous stroke or TIA 1.12 0.71 1.08
Death from any cause
Previous stroke or TIA 3.24 4.39 4.58
0.06 0.50
No previous stroke or TIA 3.87 3.45 4.02
Haemorrhagic stroke
Previous stroke or TIA 0.08 0.20 0.77
0.09 0.97
No previous stroke or TIA 0.13 0.07 0.29
0.5 1.0 1.5 0.5 1.0 1.5
Favours Favours Favours Favours
110 mg warfarin 150 mg warfarin
dabigatran dabigatran
 Effect of dabigatran was consistent with regard to reduction of the efficacy
endpoint (150 mg) as well as to reduction of ICH (both doses)
Diener HC et al. Lancet Neurol 2010;9:1157–63

55. Apixaban vs Warfarin in ARISTOTLE (Eastone et al. Lancet Neurology 2011)
Effect of Apixaban was consistent (and possibly higher) for reduction of the safety endpoints in pts with previous stroke
Eastone et al. Lancet Neurology 2011

56. Nuovi Anticoagulanti Orali non VK Antagonisti
Vantaggi
 Dose – risposta prevedibile : dose fissa giornaliera
 Non necessità di monitoraggio dell’anticoagulazione
 Elevata efficacia e sicurezza
 Significativa riduzione del rischio emorragico
 Inizio e termine d’azione rapidi: non necessità di bridge con
eparina
 Minime interazioni farmacologiche
 Assenza di interazioni alimentari
Di Pasquale G, Riva L, G Ital Cardiol 2011; 12: 556-65

57. Nuovi Anticoagulanti Orali non VK Antagonisti
Svantaggi
 Aggiustamento empirico del dosaggio
 Necessità di nuovi test laboratoristici da eseguire in caso di
eventi emorragici o trombotici
 Difficoltà di valutare l’aderenza del paziente alla terapia
 Mancanza di antidoto in caso di sovradosaggio o emorragie
 Inizio e termine d’azione rapidi: potenziale svantaggio nei
pazienti con bassa aderenza terapeutica
 Possibile ridotta consapevolezza della terapia da parte del
paziente
 Costo elevato
Di Pasquale G, Riva L, G Ital Cardiol 2011; 12: 556-65

58. Nuovi farmaci anticoagulanti
Problemi Aperti
 Aderenza/persistenza
 Come monitorare
 Range terapeutico
 Antidoto
 Gestione dell’emorragia
 Safety a lungo termine

59. Possible reasons to AF keep pts on warfarin (1)
 GOOD LEVEL OF CONTROL - Because of the
twice daily dosing (D, A) and greater risk of
nonhemorrhagic side effects (D) patients already
taking warfarin with excellent INR control may have
little to gain by switching to dabigatran. Patient values
and preferences should influence the decision to initiate
dabigatran.
 RENAL FAILURE - Warfarin remains the treatment
of choice for patients with a calculated creatinine
clearance close to or less than 30 mL/min.
 MECHANICAL HEART VALVE
REPLACEMENT Schulman and Crowther 2012

60. Possible reasons to keep AF patients on warfarin (2)
GI DISEASE AND ELDERLY - When extracranial
bleeding is of particular concern, for example in patients over
75 yrs with a history of recurrent extracranial bleeding or
with preexisting coagulopathy, warfarin may be preferable vs D
because this drug is rapidly reversible. This concern may not be
true for the factor Xa inhibitors (?)
Patients with intestinal angiodysplasia, IBD, or diverticulosis, or
those with a history of other forms of GI bleeding may experience
a deterioration on treatment with D or R
Discontinuation of D was more frequent as a result of GI
distress, and over 11% of pts complained of dyspepsia
(attributed to both tartaric acid contained in the capsule and to a
high concentration of active drug in the colon).
Schulman and Crowther 2012

61. Possible reasons to keep AF patients on warfarin (3)
POOR COMPLIANCE (?) – However, with novel
agents, the first marker of noncompliance is probably
stroke or other thrombotic complications.
COSTS (?) - Many patients who do not have drug
coverage will probably remain on warfarin, despite
evidence that from a broader perspective novel agents
are cost-neutral or cost-effective in many settings
Schulman and Crowther 2012

62. Possible reasons to keep AF patients on NOAs
 UNEXPLAINED POOR WARFARIN CONTROL - Warfarin-experienced
patients who continue to have variable INR results, corresponding to a TTR of
less than 65%, have lower rates of stroke and other complications when treated
with D 150 mg twice daily
 POOR LEVEL OF CONTROL BECAUSE OF UNAVOIDABLE DRUG-
DRUG INTERACTION – frequent need for antibiotic treatment,
chemotherapy, amiodarone, frequent use of acetaminophen, azathioprine, or a
large number of concomitant medications, particularly if the exposure to these
medications varies
 HISTORY OF INTRACRANIAL BLEEDING
 NEW PATIENTS ON AF OR PATIENTS NEVER PRESCRIBED AVK
 LOGISTIC PROBLEMS
 PTS WILLING TO RECEIVE NOA
Modified from Schulman and Crowther 2012

63. ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran) JACC 2011

64. stroke risk reduction with antithrombotic therapy in AF
MT
Granger CB, Circulation 2012

65. Exclusion criteria in AF trials

66. Apixaban vs Warfarin in ARISTOTLE
 Effect of Apixaban was consistent with regard to reduction of the safety endpoint
Granger NEJM 2011

67. CHADS2 subgroup analysis:
intracranial bleeding
 Effect of dabigatran was consistent (no significant interaction with treatment)
Dabigatran 110 mg BID Dabigatran 150 mg BID
vs. warfarin vs. warfarin
Annual rate (%)
D 110 D 150 P=0.70 P=0.82
CHADS2 mg mg Warfari
score BID BID n
0-1 0.20 0.20 0–1
2 0.22 0.26 0.69
3–6 0.26 0.52 1.07
0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0
Dabigatran Warfarin Dabigatran Warfarin
better better better better
BID = twice daily; D = dabigatran; P values for interaction
Oldgren J et al. Ann Int Med 2011;155:660−9

68. New anticoagulants and CRF
 Longer half-life
 Monitoring of renal function
 Doses reduction?
 Drug interaction?
Connolly SJ et al, NEJM 2009

69. Age and bleeding subgroup analysis: intracranial and
extracranial bleeding
Annual rate (%) D110 vs. warfarin D150 vs. warfarin
Warfari P P
D110 D150 RR (95% CI) RR (95% CI)
n value* value*
Intracranial bleeding
0.22 (0.11– 0.43 (0.25–
<75 yrs 0.14 0.26 0.61
0.45) 0.74)
0.37 (0.21– 0.42 (0.25–
≥75 yrs 0.37 0.41 1.00 0.28 0.91
0.64) 0.70)
Extracranial bleeding
0.72 (0.57– 0.78 (0.63–
<75 yrs 1.76 1.91 2.44
0.90) 0.98)
1.20 (0.97– 1.39 (1.13–
≥75 yrs 4.10 4.68 3.44 0.001 <0.001
1.48) 1.70)
*P value for interaction; CI = confidence interval; D110 = dabigatran 110 mg twice daily;
D150 = dabigatran 150 mg twice daily; RR = relative risk
Eikelboom JW et al. Circulation 2011;123:2362–72
Dec 2011

70. Indirect Comparisons of New Oral Anticoagulant Drugs for Efficacy and Safety
When Used for Stroke Prevention in Atrial Fibrillation
Lip GYH, JACC 2012

71. Prior stroke subgroup analysis: major clinical outcomes
in patients with or without previous stroke or TIA
Rate (% per year)
Dabigatran
110 mg 150 mg
Warfarin Interaction P Interaction P
Total bleeding
Previous stroke or TIA 14.49 16.90 18.53
0.57 0.65
No previous stroke or TIA 14.71 16.33 18.15
Major bleeding
Previous stroke or TIA 2.74 4.15 4.15
0.15 0.51
No previous stroke or TIA 2.91 3.10 3.43
Intracranial bleeding
Previous stroke or TIA 0.25 0.53 1.28
0.26 0.91
No previous stroke or TIA 0.22 0.27 0.63
Gastrointestinal major bleed
Previous stroke or TIA 1.39 2.32 1.41
0.68 0.53
No previous stroke or TIA 1.35 1.73 1.23
0.5 1.0 1.5 0.5 1.0 1.5
Favours Favours Favours Favours
110 mg warfarin 150 mg warfarin
dabigatran dabigatran
No significant interactions between primary and secondary outcomes in
patients with and without a history of prior stroke
TIA = transient ischaemic attack
Diener HC et al. Lancet Neurol 2010;9:1157–63 Dec 2011

72. SUBGROUP ANALYSIS:
HAEMORRHAGIC STROKE
Annual rate (%)
D 110 D 150 D 110 mg BID D 150 mg BID
Warfarin vs. warfarin vs. warfarin
mg BID mg BID
Age (yrs) P=0.51 P=0.75
<65 0.05 0.05 0.38
65–74 0.08 0.08 0.31
≥75 0.2 0.15 0.47
Creatinine clearance (mL/min) P=0.67 P=0.4
30–50 0.26 0.12 0.58
51–80 0.12 0.09 0.47
>80 0.03 0.08 0.13
0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0
Dabigatran Warfarin Dabigatran Warfarin
better better better better
BID = twice daily; D = dabigatran; P values for interaction.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Healey JS, et al. ACC 2010; abstr 1078-120.

73. Stroke prevention: Anticoagulant effect
Meta-analysis of stroke or systemic embolism
ICH
Relative Hazard Ratio
(95% CI) W vs Dabiga 110
W vs Placebo W vs Rivaroxa
W vs W low dose W vs Dabiga 150
W vs Aspirin W vs Apixaban 5
W vs Aspirin+Clop
W vs Ximelagatran
W vs Dabiga 110
Major bleeding
W vs Rivaroxa
W vs Dabiga 150 W vs Dabiga 110
W vs Apixaban 5 W vs Rivaroxa
W vs Dabiga 150
Favours Warfarin Favours other RX W vs Apixaban 5
Favours Warfarin Favours other RX

74. Age and bleeding subgroup analysis:
major bleeding
Annual rate (%) D110 vs. warfarin D150 vs. warfarin
RR P RR P
D110 D150 Warfarin
(95% CI) value* (95% CI) value*
0.62 0.70
<75 yrs 1.89 2.12 3.04
(0.50–0.77) (0.57–0.86)
<0.001 <0.001
1.01 1.18
≥75 yrs 4.43 5.10 4.37
(0.83–1.23) (0.98–1.42)
*P value for interaction; CI = confidence interval; D110 = dabigatran 110 mg twice daily;
D150 = dabigatran 150 mg twice daily; RR = relative risk
Eikelboom JW et al. Circulation 2011;123:2362–72
Dec 2011

75. New Anticoagulants
ORAL PARENTERAL
TF/VIIa TFPI (tifacogin)
TTP889
X IX
IXa APC (drotrecogin alfa)
VIIIa sTM (ART-123)
Va
Rivaroxaban AT Fondaparinux
Apixaban Xa
Idraparinux
Edoxaban
II
DX-9065a
Dabigatran IIa
THROMBIN
Fibrinogen Fibrin
Weitz & Bates, J Thromb Haemost 2005

76. Safety outcome
Patel MR et al, NEJM 2011

77. Dabigatran versus Warfarin in Patients with Atrial Fibrillation:
RE-LY trial
Dabigatran 110
mg BID
(N=6013)
Blinded
Patients with Primary study outcome:
Dabigatran 150 stroke or systemic
NVAF and ≥ 1
mg BID
F.U. embolism
risk factors R
(N=6075) 2 years Primary safety outcome:
(N=18113)
major bleeding
Open
Warfarin adjusted
(N=6013)
Connolly SJ et al, NEJM 2009

78. Rivaroxaban versus Warfarin in Nonvalvular atrial
fibrillation: ROCKET AF trial
Rivaroxaban 20
mg/die (or 15
mg/die if Cr Cl Primary study outcome:
Patients with 30-49 ml/min) stroke or systemic
NVAF at F.U. embolism
moderate-to-high R (N=7131)
risk of stroke Primary safety outcome:
Warfarin adjusted major and nonmajor
(N=14.264)
(N=7133) clinically relevant bleeding
Patel MR et al, NEJM 2011

79. Apixaban versus Warfarin in Patients with Atrial
Fibrillation: ARISTOTLE trial
Apixaban 5 mg BID
(2.5 mg BID if age≥80
ys, body weight<60 Kg,
Patients with AF Crea>1.5 mg/dl)
Primary study outcome:
and ≥ 1 risk
(N=9120)
F.U. stroke or systemic
factors R embolism
(N=18.201) Primary safety outcome:
Warfarin adjusted major bleeding according to
the ISTH criteria
(N=9081)
Granger CB et al, NEJM 2011

80. Bleeding
P<0.001
%
20 P=0.002
15
10
P=0.03
P<0.01 P=0.43
P=0.31
5
P=0.04 P<0.001
0
g g g g
in in in in
eed e ed e ed ed
bl bl bl le
al or g a lb
t aj in in
To M en t
t t es
ea in
hr ro
fe
-T a st
Li G
Dabigatran 110 mg Dabigatran 150 mg Warfarin
Connolly SJ et al, NEJM 2009

81. Primary Efficacy Outcome: Stroke and systemic embolism
6
Rivaroxaban Warfarin
5 Warfarin
Event
Cumulative event rate (%)
Rate 1.71 2.16
4
Rivaroxaban
3
HR 0.79 (95% CI; 0.66-0.96)
2
P-value Non-Inferiority: <0.001
1
0
0 120 240 360 480 600 720 840 960
Days since randomization
Patel MR et al, NEJM 2011

82. Study design
AF on Electrical
N = 21,107 Recording < 12 mo
Intended oral A/C
CHADS2 > 2
R
Low Exposure High Exposure Active Control
Strategy Strategy Warfarin
Edoxaban 30 mg QD Edoxaban 60 mg QD (INR 2.0 – 3.0)
Median duration of follow up 24-months
Primary Objective
Edoxaban: Therapeutically as good as Warfarin
1º EP = Stroke or SEE (Non inferiority Boundary HR 1.38)
2º EP = Stroke or SEE or All-Cause Mortality
Safety EPs = Major Bleeding, Hepatic Function
SEE=systemic embolic event
Ruff CT et al. Am Heart J. 2010;160:635-41