C. Michael Gibson, M.S., M.D

C. Michael Gibson, M.S., M.D.

Atrial Fibrillation Management

Past, Present and Future

Harvard Medical School

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)


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


PK/PD of 5 Novel Oral Agents

Ruff CR and Giugliano RP. Hot Topics in Cardiology 2010;4:7-14Ericksson BI et al. Clin Pharmacokinet 2009; 48: 1-22

Ruff CR et al. Am Heart J 2010; 160:635-41

Dabigatran Apixaban Rivaroxaban Edoxaban(DU-176b)

Betrixaban(PRT054021)

Target IIa (thrombin)

Xa Xa Xa Xa

Hrs to Cmax 2 1-3 2-4 1-2 NR

CYP Metabolism None 15% 32% NR None

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

Phase III AF TrialsRE-LY ROCKET-

AFARISTO

TLEENGAGE

AF-TIMI 48Drug Dabigatran Rivaroxaban Apixaban Edoxaban

Dose (mg)Freq

150, 110BID

20 (15*)QD

5 (2.5*)BID

60*, 30*QD

N 18,113 14,266 18,206 >21,000

Design PROBE 2x blind 2x blind 2x blind

AF criteria AF x 1< 6 mths

AF x 2(>1 in <30d)

AF or AFl x 2<12 mths

AF x 1 < 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/SEEPROBE = prospective, randomized, open-label, blinded end point evaluation VKA = Vitamin K antagonist

RE-LY Dabigatran 110 mg

Dabigatran 150 mg Warfarin

CHADS2 Mean 0-1 (%) 2 (%) 3+ (%)

2.132.634.732.7

2.232.235.232.6

2.130.937.032.1


ROCKET AF Rivaroxaban Warfarin

CHADS2 Mean 2 (%) 3 (%) 4 (%) 5 (%) 6 (%)

3.5134329132

3.5134428122

ARISTOTLE Rivaroxaban Warfarin

CHADS2 Mean 0-1 (%) 2 (%) 3+ (%)

2.134

35.830.2

2.134

35.830.2

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

3+87%

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;361:1139-1151; Granger C et al, N Eng J Med; 2011

RE-LYDabigatran 110 mg 1.53% per yearDabigatran 150 mg 1.11% per yearWarfarin 1.69% per year

ROCKET AFRivaroxaban 20mg 1.7% per yearWarfarin 2.2% per year

ARISTOTLEApixaban 5 mg 1.27% per yearWarfarin 1.60% per year

Primary Endpoint of Stroke or Systemic Embolism: Non-inferiority Analysis

p<0.001

p<0.001 p<0.001

Non Inferiorirtyp vs warfarin

ITT Analysis

Modified 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.


p<0.001ITT Analysis


HR = 0.79

HR = 0.79

HR = 0.91HR = 0.66

Hemorrhagic Stroke

Dabigatran 110 mg 0.12% / yr 0.31 <0.001Dabigatran 150 mg 0.10% / yr 0.26 <0.001

Warfarin 0.38% / yr

HRITTP-value

Rivaroxaban 20 mg 0.26% / yr 0.59 0.012*

Warfarin 0.44% / yr

ROCKET

RE-LY


*In an on treatment analysis in Rocket AF Hemorrhagic Stoke rates were 0.26% / yr for rivaroxaban and 0.44% / yr for warfarin, p=0.024. No on treatment analysis is available from RE-LY.

Apixaban 5 mg 0.24% / yr 0.51 <0.001

Warfarin 0.47% / yr

ARISTOTLE


Ischemic StrokeDabigatran 110 mg 1.34% / yr 1.20 0.35Dabigatran 150 mg 0.92% / yr 0.76 0.03

Warfarin 1.20% / yr

HRITTP-value


Warfarin 1.64% / yr

ROCKET AF

RE-LY


*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.

Aoixaban 5 mg 0.97% / yr 0.92 0.42

Warfarin 1.05% / yr

ARISTOTLE


Dabigatran now has a superiority labeling for stroke in the US

Ischemic/Unspecified StrokeD 110 mg vs.

WarfarinD 150 mg vs.

WarfarinRR =1.1195% CI = 0.89-1.40P = 0.35

RR = 0.7695% CI = 0.60-0.98P = 0.03

Years of Follow-up

Cum

ulat

ive

Haz

ard

Rat

es0.

00.

020.

040.

060.

08

0 0.5 1.0 1.5 2.0 2.5

Dabigatran110

Dabigatran150

Warfarin

Dabigatran now has a superiority labeling for stroke in the US

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)

Dabigatran 110 mg 2.71% / yr 0.8 0.003Dabigatran 150 mg 3.11% / yr 0.93 0.31

Warfarin 3.36% / yr150 mg Dabigatran vs 110 mg Dabigatran = HR of 1.16 (1.00–1.34) p = 0.052

Major BleedingHR

ITTP-valueRE-LY


Warfarin 3.45% / yr

ROCKET


*There is no ITT analysis of safety in Rocket AF. There is no on treatment analysis of safety from RE-LY.

On TreatmentP-value

P-valueApixaban 5 mg 2.13% / yr 0.69 <0.001

Warfarin 3.09% / yr

ARISTOTLE


2 g drop in 24 hours

2 g drop

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

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.”

http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/05/news_detail_001518.jsp&mid=WC0b01ac058004d5c1

http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/05/news_detail_001518.jsp&mid=WC0b01ac058004d5c1

All Cause Mortality

Dabigatran 110 mg 3.75% / yr 0.91 0.35Dabigatran 150 mg 3.64% / yr 0.88 0.051

Warfarin 4.13% / yr

HRITTp-value


Warfarin 4.91% / yr

ROCKET

RE-LY


*In an on treatment analysis in Rocket AF mortality rates were 1.87% / yr for rivaroxaban and 2.21% / yr for warfarin, p=0.073. No on treatment analysis is available from RE-LY.

Apixaban 5 mg 3.52% / yr 0.89 0.01

Warfarin 3.94% / yr

ARISTOTLE


95% CI 0.89 (0.80, 0.998)N=448 events planned, 480 in trial

Japanese RE-LY Data: Baseline Characteristics

Characteristic Overall JapanRandomized 18,113 326Mean age (years) 71.5 71.2Male (%) 63.6 76.7

CHADS2 score (mean) 0-1 (%) 2 (%) 3+ (%)

2.131.935.632.5

2.231.334.034.7

Prior stroke / SEE / TIA(%) 21.8 33.1

Prior MI (%) 16.6 5.5CHF (%) 32.0 31.0Baseline ASA (%) 39.8 35.9VKA naive (%) 50.4 56.1

Hori M, et al: Circ J 75: 800–805, 2011Connolly SJ, et al: N Engl J Med 361: 1139-1151, 2009

Region n INR ＜2.0

INR2.0-3.0

INR ＞3.0

Overall 5,789 22.2 ％ 64.4 ％ 13.5 ％

Japan 108 36.8 ％ 57.6 ％ 5.6 ％

Hori M, et al: Circ J 75: 800–805, 2011Connolly SJ, et al: N Engl J Med 361: 1139-1151, 2009

INR control 　 / Time in Therapeutic Range

For Age >=70 in Japan: INR 2.0-2.6

Stroke or Systemic Embolism

Overall Japan

% p

er y

ear

150mg bid 110mg bid (n=134/6,076) (n=183/6,015) (n=202/6,022)

% p

er y

ear

150mg bid 110mg bid (n=1/111) (n=12/107) (n=4/108)

RR 0.90 (95% CI: 0.74-1.10)

RR 0.65 (95% CI: 0.52-0.81)

RR 0.52 (95% CI: 0.10-2.84)

RR 0.25 (95% CI: 0.03-2.27)

Connolly SJ, et al: N Engl J Med 361: 1139-1151, 2009 Connolly SJ, et al: N Engl J Med 363: 1875-1876, 2010

Hori M, et al: Circ J 75: 800–805, 2011

Bleeding Events in Japanese SubjectsEvent (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) 1 (0.67)

Intracranial 1 (0.69) 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

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.

Summary / Japanese patients

Hori M, et al: Circ J 75: 800–805, 2011

Warfarin （ 2002 ～）

2.5 mg 2.5 mg 1.5mg

nose bleed dementia Strokedementia

2.16

1.541.36

2.1 2.15

0.91

2.13

3.53

1.35

0.78 0.81 0.87

1.16

0.81

0

1

2

3

4

2004Jan Feb Mar Apr May Oct Nov Dec

2005Jan Feb Mar Apr

PT-I

NR

2.5 mg

dementia

aspirin

Age 81 Female （ Living alone, ADL ： independent ）Chronic AF 　 HT(-), No heart disease, DM(-), LAD 43mm

29th 4,2005 14th 5,2005

Age 81 Female （ Living alone, ADL ： independent ）Chronic AF 　 HT(-), No heart disease, DM(-), LAD 43mm ）

mRS by subtype of brain infaction （ HIROSAKI Stroke and Rehabilitation Center ）

n=768 （ Oct, 2005 ～ Jan, 2008 ）

0 　　　 20 　　　 40 　　 60 　　　 80 　　 100 (%)

0

1

2

3

4

5

6

No symptoms

Dead

Bedridden

Able to carry out all usual activities

Able to look after own affairs without assistance

Requires some help, but able to walk unassisted

Unable to walk unassisted

m-Rankinscale

31% 54%

Lacunar（ n=215 ）

Atherothrombotic infarction

（ n=308 ）

Cerebral embolism （ n=245

）

Ken Okumura, Norihumi Metoki, Jyoji Hagii 　 Japanese Journal of Electrocardiology 2011;31:292-296

AF(+)n=139

（ 52%）

AF(-)n=128

（ 48%）

ECG on admission

Prevalence of AF among Cerebral embolism patients:267 consecutive patients during 2008-2009

（ HIROSAKI Stroke and Rehabilitation Center ）

Data from previous Dr & ECG during hospitalization

AF(-)n=67

（ 25%）Sustained AF

n=120（ 45% ）paroxysmal

AFn=80

（ 30% ）

Ken Okumura, Norihumi Metoki, Jyoji Hagii 　 Japanese Journal of Electrocardiology 2011;31:292-296

Severity of stroke by AF typeSustained AF VS Paroxysmal AF VS Not defined AF

Sustained（ n=120 ）

Paroxysmal（ n=80 ）

Not defined AF

（ n=67 ）

Percentage of patients with internal carotid artery stenosis

（ P ＝ NS ）

Percentage of patients with mRS = 4,5,6

（ P ＝ NS ）

0 20 40 60 80 100% 0 20 40 60 80 100%

*Patients with acute stroke within 3 hours of onset were treated with tPA

CHADS2 Score and Severity of stroke

CHADS2=0,1 Score （ n=41 ） VS CHADS2=2-6 Score （ n=159 ）

0 20 40 60 80 100%

CHADS2=0,1

（ n=41 ） 2417

73 86

329

34 125

0 20 40 60 80 100%

CHADS2=2-

6 （ n=159

）

Percentage of patients with internal carotid artery stenosis

（ P ＝ NS ）

Percentage of patients with mRS = 4,5,6

（ P ＝ NS ）

CHADS2 スコア

(%)

1.9% 2.8% 4.0%5.9%

8.5%12.5%

18.2%

Incidence fo strokeNational Registry of AF

20

40

60

80

100

0

(cases)

The Japanese Society of Electrocardiology J-RHYTHM Registry

CHADS2 Score of registered AF patients (n=7,937)

Net Clinical Benefit in ATRIA Study(Singer DE, et al. Ann Intern Med 2009;151:297-305)

13559 adults with non-valvular atrial fibrillation at Kaiser Permanente Northern California（ 73 years median age; Male 57%; more than 66000 personyearsof observation; 53% of patients were receiving warfarin treatment. ）

→ 1092 thromboembolic events, 299 intracranial hemorrhagic events

Netclinical benefit of patients with Prior Stroke= 2.48% per year

Net clinical benefit of warfarin = 0.68% per year

Net Clinical Benefit=(TE rateoff warfarin − TE rateon warfarin) − 1.5 × (ICH rateon warfarin − ICH rateoff warfarin)

Intracranial hemorrhage rate

0Dabigatran

150mg BID（ n=38/6,076 ）（ n=90/6,022 ）

Warfarin110mg BID

（ n=27/6,015 ）

Dabigatran

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 ）P ＜ 0.001

1.0

0.320.23

0.76

RRR59 ％

RRR70％

Eve

nt r

ate

（%

per

yea

r）

Connolly SJ, et al.: N Engl J Med 361, 1139-1151, 2009Connolly SJ, et al.: N Engl J Med 363, 1875-1876, 2010

Intracranial hemorrhage: Hemorrhagic Stroke (Intracerebral hemorrhage), Subdural hematoma and Subarachnoid hemorrhage

CHADS2 Score

Heart failure 1pointHypertension 1point≥75 years old 1pointDiabetes 1pointHistory of cerebral infarction or TIA 2points

Mitral stenosisor

mechanical valve

1point≥2points

Other risk factors　 Cardiomyopathy　 65 to 74 years old　 Female patients　 Coronary heart disease　 Thyrotoxicosis

Non-valvular AF

WarfarinINR2.0 ～ 3.0

Recommended

WarfarinINR2.0 to 3.0 for < 70 years oldINR1.6 to 2.6 for ≥ 70 years old

Recommended

Dabigatran


Considered

Dabigatran


Considered

Dabigatran

Recommended

Ogawa S, et al: Circ J 75: 2719–2721, 2011

Urgent Statement on Antithrombotic Therapy of Atrial Fibrillation :

JCS Guideline Statement (Aug.2011)

Documents

C. Michael Gibson, M.S., M.D