1. Atrial Fibrillation Management Past, Present and Future
C. Michael Gibson, M.S., M.D.
Atrial Fibrillation Management
Past, Present and Future
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; 160:635-41

5. Phase III AF Trials RE-LY ROCKET-AF ARISTO TLE 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
2x blind
AF criteria
AF x 1
< 6 mths
AF x 2
(>1 in <30d)
AF or AFl x 2
<12 mths
< 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 Dabigatran 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
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
Non Inferiorirty
p vs warfarin
RE-LY
Dabigatran 110 mg 1.53% per year
Dabigatran 150 mg 1.11% per year
Warfarin % per year
ROCKET AF
Rivaroxaban 20mg 1.7% per year
Warfarin 2.2% per year
ARISTOTLE
Apixaban 5 mg 1.27% per year
Warfarin 1.60% per year
ITT Analysis
HR = 0.91
p<0.001
HR = 0.66
p<0.001
Modified ITT
HR = 0.79
p<0.001
ITT Analysis
HR = 0.79
p<0.001
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 ITT P-value RE-LY HR
Dabigatran 110 mg 0.12% / yr <0.001
Dabigatran 150 mg 0.10% / yr <0.001
Warfarin % / yr
ROCKET
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 ITT P-value HR RE-LY
Dabigatran 110 mg 1.34% / yr
Dabigatran 150 mg 0.92% / yr
Warfarin % / 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
Aoixaban 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
0.08
D 110 mg vs. Warfarin
D 150 mg vs. Warfarin
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
Dabigatran110
0.04
Warfarin
0.02
Dabigatran150
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. Major Bleeding RE-LY HR Dabigatran 110 mg 2.71% / yr 0.8 0.003
ITT
P-value
RE-LY HR
Dabigatran 110 mg % / yr
Dabigatran 150 mg 3.11% / yr
Warfarin % / yr
150 mg Dabigatran vs 110 mg Dabigatran = HR of 1.16 (1.00–1.34) p = 0.052
On Treatment
P-value
ROCKET
Rivaroxaban 20 mg 3.60% / yr *
Warfarin % / yr
2 g drop
*There is no ITT analysis of safety in Rocket AF. There is no on treatment analysis of safety from RE-LY.
P-value
ARISTOTLE
Apixaban 5 mg 2.13% / yr <0.001
Warfarin % / 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

14. 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

15. 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.”

16. All Cause Mortality ITT p-value RE-LY HR
Dabigatran 110 mg 3.75% / yr
Dabigatran 150 mg 3.64% / yr
Warfarin % / yr
ROCKET
Rivaroxaban 20 mg 4.52% / yr *
Warfarin 4.91% / yr
ARISTOTLE
Apixaban 5 mg 3.52% / yr
Warfarin % / 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

17. 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

18. 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

19. Stroke or Systemic Embolism
Overall
Japan
% per year
150mg bid mg bid
(n=134/6,076) (n=183/6,015) (n=202/6,022)
% per year
150mg bid mg bid
(n=1/111) (n=12/107) (n=4/108)
RR 0.65 (95% CI: )
RR 0.25 (95% CI: )
RR 0.90
(95% CI: )
RR 0.52
(95% CI: )
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

20. 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

21. 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

22. Age 81 Female（Living alone, ADL：independent ）
Chronic AF　HT(-), No heart disease, DM(-), LAD 43mm
dementia
nose bleed
dementia
dementia
Stroke
Warfarin（2002～） 4
2.5 mg
2.5 mg
aspirin
1.5mg
2.5 mg
3.53 3
2.16
2.1
2.15
2.13
PT-INR 2
1.35
1.54
1.16
1.36 1
0.91
0.81
0.87
0.81
0.78
2004
Jan
2005
Jan
Feb
Mar
Apr
May
Oct
Nov
Dec
Feb
Mar
Apr

23. Age 81 Female（Living alone, ADL：independent ）
Chronic AF　HT(-), No heart disease, DM(-), LAD 43mm）
29th 4,2005
14th 5,2005

24. mRS by subtype of brain infaction （HIROSAKI Stroke and Rehabilitation Center）
m-Rankin
scale
n=768 （Oct, 2005～Jan, 2008）
No symptoms
Lacunar
（n=215）
Able to carry out all usual activities 1
Able to look after own affairs without assistance 2
Atherothrombotic
infarction
（n=308）
Requires some help, but able to walk unassisted 3
Unable to walk unassisted
31%
54% 4
Cerebral
embolism
（n=245） 5
Bedridden 6
Dead
0　　　 　　 　40　　 　　 　80　　 (%)
Ken Okumura, Norihumi Metoki, Jyoji Hagii　Japanese Journal of Electrocardiology 2011;31: 24

25. Prevalence of AF among Cerebral embolism patients:
267 consecutive patients during
（HIROSAKI Stroke and Rehabilitation Center）
Data from previous Dr &
ECG during hospitalization
Sustained AF
（45%）
paroxysmal AF
（30%）
ECG on admission
Ken Okumura, Norihumi Metoki, Jyoji Hagii　Japanese Journal of Electrocardiology 2011;31: 25

26. Severity of stroke by AF type
Sustained AF VS Paroxysmal AF VS Not defined AF
Percentage of patients with internal
carotid artery stenosis
（P＝NS）
Percentage of patients with mRS = 4,5,6
（P＝NS）
Sustained
（n=120）
Paroxysmal
（n=80）
Not defined AF
（n=67） % %
*Patients with acute stroke within 3 hours of onset were treated with tPA 26

27. CHADS2 Score and Severity of stroke
CHADS2=0,1 Score（n=41） VS CHADS2=2-6 Score（n=159）
Percentage of patients with internal
carotid artery stenosis
（P＝NS）
Percentage of patients with mRS = 4,5,6
（P＝NS）
CHADS2=0,1（n=41） 9 32 17 24
CHADS2=2-6（n=159） 34
125 73 86 % % 27

28. J-RHYTHM Registry CHADS2スコア J-RHYTHM Registry
The Japanese Society of Electrocardiology
J-RHYTHM Registry
CHADS2 Score of registered AF patients (n=7,937)
J-RHYTHM Registry
(%) 20 40 60 80
100
(cases)
1.9%
2.8%
4.0%
5.9%
8.5%
12.5%
18.2%
Incidence fo stroke
National Registry of AF
CHADS2スコア

29. → 1092 thromboembolic events, 299 intracranial hemorrhagic events
Net Clinical Benefit in ATRIA Study
(Singer DE, et al. Ann Intern Med 2009;151: )
13559 adults with non-valvular atrial fibrillation at Kaiser Permanente Northern California
（ 73 years median age; Male 57%; more than personyears
of observation; 53% of patients were receiving warfarin treatment. ）
→ 1092 thromboembolic events, 299 intracranial hemorrhagic events
Net clinical benefit of warfarin = 0.68% per year
Netclinical benefit of patients with Prior Stroke= 2.48% per year
Net Clinical Benefit=(TE rateoff warfarin − TE rateon warfarin) − 1.5 × (ICH rateon warfarin − ICH rateoff warfarin)

30. Intracranial hemorrhage rate
Intracranial hemorrhage: Hemorrhagic Stroke (Intracerebral hemorrhage), Subdural hematoma and Subarachnoid hemorrhage
RR 0.41 （95％ CI: 0.28–0.60）
P＜0.001
0.8
0.6
0.4
0.2
RR 0.30 （95％ CI: 0.19–0.45）
1.0
0.32
0.23
0.76
RRR
59％
70％
Event rate （% per year）
頭蓋内出血の発現率は、ワルファリン群で0.76％ /年（90/6，022例）であったのに対し、ダビガトラン150mg×2/日群で0.32％ /年（38/6，076例）、ダビガトラン110mg×2/日群で0.23％ /年（27/6，015例）であり、ダビガトランの両群ともにワルファリン群に比べ有意な低下が認められました。
ダビガトラン150mg×2/日群でのリスク低下率は59％、ダビガトラン110mg×2/日群でのリスク低下率は70％でした。
有効性でワルファリンと同等かそれ以上の成績を残した薬剤において、抗凝固薬投与中に最も注意しなくてはならない頭蓋内出血の発現率が減少するという結果は意外であったし、それによりこの薬剤への期待は一層高まったのではないでしょうか。
（参考）
頭蓋内出血の定義：
出血性脳卒中（脳内出血）、クモ膜下出血および硬膜下出血
Dabigatran
Dabigatran
Warfarin
150mg BID
（n=38/6,076）
110mg BID
（n=27/6,015）
（n=90/6,022）
Connolly SJ, et al.: N Engl J Med 361, , 2009
Connolly SJ, et al.: N Engl J Med 363, , 2010

31. Urgent Statement on Antithrombotic Therapy of Atrial Fibrillation : JCS Guideline Statement (Aug.2011)
Mitral stenosis or
mechanical valve
Non-valvular AF
CHADS2 Score
Heart failure point
Hypertension point
≥75 years old point
Diabetes point
History of cerebral infarction or TIA 2points
Other risk factors
　Cardiomyopathy
　65 to 74 years old
　Female patients
　Coronary heart disease
　Thyrotoxicosis
≥2points
1point
Recommended
Recommended
Considered
Considered
Warfarin
INR2.0～3.0
Warfarin
INR2.0 to 3.0 for < 70 years old
INR1.6 to 2.6 for ≥ 70 years old
Warfarin
INR2.0 to 3.0 for < 70 years old
INR1.6 to 2.6 for ≥ 70 years old
Warfarin
INR2.0 to 3.0 for < 70 years old
INR1.6 to 2.6 for ≥ 70 years old
Dabigatran
Recommended
Dabigatran
Dabigatran
Ogawa S, et al: Circ J 75: 2719–2721, 2011