1. Atrial Fibrillation Management Past, Present and Future
C. Michael Gibson, M.S., M.D.
Harvard Medical School

2. Conflict of Interest Statement
Dr. Gibson has received research grant support and consulting monies from all major manufacturers of antithrombin and antiplatelet agents including all sponsors of Factor Xa inhibitors (BMS, Pfizer, Johnson and Johnson, Portola, DSI) and Factor II inhibitors (Boehringer Ingelheim)
C. Michael Gibson, M.S., M.D.

3. Atrial Fibrillation and Stroke
AF responsible for 1/6 of all strokes
Warfarin reduces stroke in AF by 64%
－ significant increase in intracranial and other hemorrhage
－ Difficult to use
Only 50% of eligible patients receive warfarin
An alternative treatment is needed
C. Michael Gibson, M.S., M.D.

4. PK/PD of 5 Novel Oral Agents
Dabigatran
Apixaban
Rivaroxaban
Edoxaban
(DU-176b)
Betrixaban
(PRT054021)
Target
IIa (thrombin) Xa
Hrs to Cmax 2
1-3
2-4
1-2 NR
CYP Metabolism
None
15%
32%
Half-Life
12-14h
8-15h
9-13h
8-10h
19-20h
Renal Elimination
80%
25%
66%
35%
<5%
CYP = cytochrome P450; NR = not reported
Ruff CR and Giugliano RP. Hot Topics in Cardiology 2010; 4: 7-14
Ericksson BI et al. Clin Pharmacokinet 2009; 48: 1-22
Ruff CR et al. Am Heart J 2010; 160:

5. Phase III AF trials RE-LY ROCKET AF ARISTOTLE ENGAGE AF-TIMI 48 Drug
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Dose (mg)
Freq
150, 110
BID
20 (15*) QD
5 (2.5*)
60*, 30* N
18,113
14,266
18,206
>21,000
Design
PROBE
2 x blind
AF criteria
AF x 1
<6 mths
AF x 2
(≥ 1 in <30d)
AF or AFI x 2
<12 mths
% VKA naive
50%
38%
43%
40% goal
*Dose adjusted in patients with ↓drug clearance. **Max of 10% with CHADS-2 score = 2 and no stroke/TIA/SEE
PROBE = prospective, randomized, open-label, blinded end point evaluation VKA = Vitamin K antagonist

6. RE-LY ROCKET AF ARISTOTLE Dabigatran 110 mg 150 mg Warfarin
CHADS2 Mean
0-1 (%)
(%)
3+ (%)
2.1
32.6
34.7
32.7
2.2
32.2
35.2
30.9
37.0
32.1
ROCKET AF
Rivaroxaban
Warfarin
CHADS2 Mean
2 (%)
3 (%)
4 (%)
5 (%)
6 (%)
3.5 13 43 29 2 44 28 12 3+
87%
ARISTOTLE
Rivaroxaban
Warfarin
CHADS2 Mean
0-1 (%)
2 (%)
3+ (%)
2.1 34
35.8
30.2
C. Michael Gibson, M.S., M.D.
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009; 361: ; Granger C et al, N Eng J Med; 2011

7. Comparison of Trial Metrics 67% warfarin-experienced
RE-LY
ROCKET AF
ARISTOTLE
Time in Therapeutic Range (TTR)
64%
67% warfarin-experienced
61% warfarin-naïve
Mean 55%
Median 58%
62%
C. Michael Gibson, M.S., M.D.
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009; 361: ; Granger C et al, N Eng J Med; 2011

8. Primary Endpoint of Stroke or Systemic Embolism: Non-inferiority Analysis
p vs warfarin HR
RE-LY
　Dabigatran 110 mg 1.53% / yr 0.91 <0.001
　Dabigatran 150 mg 1.11% / yr <0.001
　Warfarin 1.69% / yr
(ITT)
ROCKET AF
　Rivaroxaban 20 mg 1.7% / yr <0.001
　Warfarin 2.2% / yr
(Modified ITT)
ARISTOTLE
　Apixaban 5 mg 1.27% / yr <0.001
　Warfarin 1.60% / yr
(ITT)
No ITT analysis is available for non-inferiority in ROCKET AF. An on treatment or per-protocol analysis is generally performed in the assessment of non-inferiority. If numerous patients come off of study drug, this biases the trial towards a non-inferior result in an ITT analysis. This is the basis for performing a per-protocol analysis in a non-inferiority assessment.
C. Michael Gibson, M.S., M.D.
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009; 361: ; Granger C et al, N Eng J Med; 2011

9. Hemorrhagic Stroke RE-LY Dabigatran 110 mg 0.12% / yr 0.31 <0.001
ITT
p vs warfarin HR
RE-LY
　Dabigatran 110 mg 0.12% / yr <0.001
　Dabigatran 150 mg 0.10% / yr <0.001
　Warfarin 0.38% / yr
ROCKET AF
　Rivaroxaban 20 mg 0.26% / yr *
　Warfarin 0.44% / yr
ARISTOTLE
　Apixaban 5 mg 0.24% / yr <0.001
　Warfarin 0.47% / yr
*In an on treatment analysis in ROCKET AF Hemorrhagic Stoke rates were 0.26% / yr for rivaroxaban and 0.44% / yr for warfarin, p= No on treatment analysis is available from RE-LY.
C. Michael Gibson, M.S., M.D.
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009; 361: ; Granger C et al, N Eng J Med; 2011

10. Ischemic Stroke RE-LY Dabigatran 110 mg 1.34% / yr 1.20 0.35
ITT
p vs warfarin HR
RE-LY
　Dabigatran 110 mg 1.34% / yr
　Dabigatran 150 mg 0.92% / yr
　Warfarin 1.20% / yr
Dabigatran now has a superiority labeling for stroke in the US
ROCKET AF
　Rivaroxaban 20 mg 1.62% / yr *
　Warfarin 1.64% / yr
ARISTOTLE
　Apixaban 5 mg 0.97% / yr
　Warfarin 1.05% / yr
*In an on treatment analysis in ROCKET AF Ischemic Stoke rates were 1.34% / yr for rivaroxaban and 1.42% / yr for warfarin, p=0.58. No on treatment analysis is available from RE-LY.
C. Michael Gibson, M.S., M.D.
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009; 361: ; Granger C et al, N Eng J Med; 2011

11. Ischemic/Unspecified Stroke Cumulative Hazard Rates
0.08
Dabigatran 110 mg
vs. Warfarin
Dabigatran 150 mg
RR =1.11
95% CI =
P = 0.35
RR = 0.76
95% CI =
P = 0.03
0.06
Dabigatran now has a superiority labeling for stroke in the US
Cumulative Hazard Rates
0.04
Dabigatran110mg
Warfarin
0.02
Dabigatran150mg
0.0
0.5
1.0
1.5
2.0
2.5
Years of Follow-up

12. Hazard ratio vs. warfarin
Revised US Label
The contributions of components of the composite endpoint, including stroke by subtype, are shown in Table 5. The treatment effect was primarily a reduction in stroke. PRADAXA 150 mg twice daily was superior in reducing ischemic and hemorrhagic stroked relative to warfarin.
PRADAXA　
150 mg twice daily
Warfarin
Hazard ratio vs. warfarin
(95% CI)
Patients randomized
6076
6022
Stroke
122
186
0.64 (0.51, 0.81)
Ischemic stroke
103
134
0.75 (0.58, 0.97)
Hemorrhagic stroke 12 45
0.26 (0.14, 0.49)
Systemic embolism 13 21
0.61 (0.30, 1,21)

13. Dabigatran 150 mg BID preferable to dose- adjusted VKA* for:
2012 ACCP guidelines for antithrombotic therapy in AF: recommendations for dabigatran
Dabigatran 150 mg BID preferable to dose- adjusted VKA* for:
patients at intermediate or high risk of stroke (CHADS2 ≥1)
secondary prevention of cardioembolic stroke
Dabigatran as an alternative to dose-adjusted VKA or LMWH in patients undergoing elective cardioversion
*Target range for international normalized ratio: 2.0–3.0
LMWH = low-molecular-weight heparin; VKA = vitamin K antagonist
You JY et al. Chest 2012;141;e531S–e575S

14. 2012 ACCP guidelines for antithrombotic therapy in patients with AF
Patient features
Recommended antithrombotic therapy
Low risk of stroke
(e.g. CHADS2 = 0)
None (rather than antithrombotic therapy)
Intermediate risk of stroke (e.g. CHADS2 = 1)
Oral anticoagulation (rather than no therapy, Aspirin, or Aspirin + clopidogrel)
Dabigatran 150 mg BID (rather than dose-adjusted VKA*)
High risk of stroke (e.g. CHADS2 = 2)
Previous stroke/TIA
BID = twice daily; TIA = transient ischaemic attack; VKA = vitamin K antagonist *Target range for international normalized ratio: 2.0–3.0
You JY et al. Chest 2012;141;e531S–e575S

15. Major Bleeding RE-LY Dabigatran 110 mg 2.71% / yr 0.8 0.003
ITT
p vs warfarin HR
RE-LY
　Dabigatran 110 mg 2.71% / yr
　Dabigatran 150 mg 3.11% / yr
　Warfarin 3.36% / yr
150 mg Dabigatran vs 110 mg Dabigatran = HR of 1.16 (1.00–1.34) p = 0.052
ROCKET AF
　Rivaroxaban 20 mg 3.60% / yr *
　Warfarin 3.45% / yr
(On Treatment)
2 g drop
*There is no ITT analysis of safety in ROCKET AF. There is no on treatment analysis of safety from RE-LY.
ARISTOTLE
　Apixaban 5 mg 2.13% / yr <0.001
　Warfarin 3.09% / yr
2 g drop in 24 hours
C. Michael Gibson, M.S., M.D.
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009; 361: ; Granger C et al, N Eng J Med; 2011

16. Post Marketing Surveillance
Excess bleeding reported in some countries for Dabigatran compared to coumadin.
Most likely this is due to the fact that bleeding with warfarin was expected, and it was not expected with Dabigatran.

17. Post Marketing Surveillance
The EMA found that “the frequency of occurrence of fatal bleedings with Pradaxa seen in post-marketing data was significantly lower than what was observed in the clinical trials that supported the authorisation of the medicine”
“On the basis of the available evidence, the Committee for Medicinal Products for Human Use (CHMP) concluded that the benefits of Pradaxa continue to outweigh its risks and that it remains an important alternative to other blood-thinning agents.”

18. All Cause Mortality RE-LY Dabigatran 110 mg 3.75% / yr 0.91 0.35
ITT
p vs warfarin HR
RE-LY
　Dabigatran 110 mg 3.75% / yr
　Dabigatran 150 mg 3.64% / yr
　Warfarin 4.13% / yr
ROCKET AF
　Rivaroxaban 20 mg 4.52% / yr *
　Warfarin 4.91% / yr
ARISTOTLE
　Apixaban 5 mg 3.52% / yr
　Warfarin 3.94% / yr
95% CI 0.89 (0.80, 0.998)
N=448 events planned, 480 in trial
*In an on treatment analysis in ROCKET AF mortality rates were 1.87% / yr for rivaroxaban and 2.21% / yr for warfarin, p= No on treatment analysis is available from RE-LY.
C. Michael Gibson, M.S., M.D.
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009; 361: ; Granger C et al, N Eng J Med; 2011

19. Japanese RE-LY Data: Baseline Characteristics
Overall
Japan
Randomized
18,113
326
Mean age (years)
71.5
71.2
Male (%)
63.6
76.7
CHADS2 score
(mean)
0-1 (%)
(%)
3+ (%)
2.1
31.9
35.6
32.5
2.2
31.3
34.0
34.7
Prior stroke / SEE / TIA(%)
21.8
33.1
Prior MI (%)
16.6
5.5
CHF (%)
32.0
31.0
Baseline ASA (%)
39.8
35.9
VKA naive (%)
50.4
56.1
Over all : calculated from NEJM, 2009, 361, 12
Hori M, et al: Circ J 75: 800–805, 2011
Connolly SJ, et al: N Engl J Med 361: , 2009

20. INR control / Time in Therapeutic Range
Region n
INR＜2.0
INR
INR＞3.0
Overall
5,789
22.2％
64.4％
13.5％
Japan
108
36.8％
57.6％
5.6％
For Age >=70 in Japan: INR
Hori M, et al: Circ J 75: 800–805, 2011
Connolly SJ, et al: N Engl J Med 361: , 2009

21. Stroke or Systemic Embolism
Overall
Japan
5.0
5.0
RR 0.65 (95％ CI: )
RR 0.25 (95% CI: )
4.0
4.0
RR 0.90
(95％ CI: )
RR 0.52
(95% CI: )
3.0
3.0
% per year
% per year
2.65
2.0
2.0
1.71
1.54
1.38
1.0
1.11
1.0
0.67
Dabigatran
150mg bid
(n=134/6,076)
Dabigatran
110mg bid
(n=183/6,015)
Warfarin
(n=202/6,022)
Dabigatran
150mg bid
(n=1/111)
Dabigatran
110mg bid
(n=2/107)
Warfarin
(n=4/108)
Connolly SJ, et al: N Engl J Med 361: , 2009
Connolly SJ, et al: N Engl J Med 363: , 2010
Hori M, et al: Circ J 75: 800–805, 2011

22. Bleeding Events in Japanese Subjects
Event (yearly rate)
110 mg bid (N=107)
150 mg bid
(N=111)
Warfarin
(N=108)
Major bleeding
8 (5.53)
*(2.87)
5 (3.33)
*(3.32)
5(3.31)
*(3.57)
Life threatening
1 (0.69)
3 (2.00)
2 (1.33)
Gastrointestinal
3 (2.11)
1 (0.67)
Intracranial
1 ( 0.67)
1 (0.66)
Minor bleeding
35 (24.19)
*(13.16)
50 (33.26)
*(14.85)
50 (33.14)
*(16.37)
Any bleeding
(major or minor)
40 (27.64)
*(14.74)
52 (34.59)
*(16.56)
51 (33.81)
*(18.37)
* Overall
Hori M, et al: Circ J 75: 800–805, 2011

23. Summary / Japanese patients
The demographics of the Japanese subgroup differ from the overall population in prior stroke and MI of RE-LY but the overall risk score is similar.
The stroke and systemic embolism frequencies in the Japanese subgroup are comparable with the overall RE-LY results.
The major bleeding rates of 150mg bid in the Japanese subgroups, are generally consistent with the overall population.
The minor bleeding rates of Japanese subgroups, are higher than the overall population.
Hori M, et al: Circ J 75: 800–805, 2011