c. michael gibson, m.s., m.d
DESCRIPTION
Atrial Fibrillation Management Past, Present and Future. C. Michael Gibson, M.S., M.D. Harvard Medical School. Conflict of Interest Statement. - PowerPoint PPT PresentationTRANSCRIPT
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C. Michael Gibson, M.S., M.D.C. Michael Gibson, M.S., M.D.
Atrial Fibrillation Management
Past, Present and Future
Harvard Medical School
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Conflict of Interest StatementConflict 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.
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Atrial Fibrillation and StrokeAtrial 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.
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PK/PD of 5 Novel Oral AgentsPK/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
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Phase III AF TrialsPhase III AF Trials
RE-LY ROCKET-AF
ARISTOTLE
ENGAGE AF-TIMI 48
Drug 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/SEE
PROBE = prospective, randomized, open-label, blinded end point evaluation VKA = Vitamin K antagonist
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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
C. Michael Gibson, M.S., M.D.
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%
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Comparison of Trial MetricsComparison 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
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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.
C. Michael Gibson, M.S., M.D.
p<0.001ITT Analysis
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
HR = 0.79
HR = 0.79
HR = 0.91
HR = 0.66
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Hemorrhagic StrokeHemorrhagic 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
C. Michael Gibson, M.S., M.D.
*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
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
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Ischemic StrokeIschemic Stroke
Dabigatran 110 mg 1.34% / yr 1.20 0.35Dabigatran 150 mg 0.92% / yr 0.76 0.03
Warfarin 1.20% / yr
HRITTP-value
Rivaroxaban 20 mg 1.62% / yr 0.99 0.92*
Warfarin 1.64% / yr
ROCKET AF
RE-LY
C. Michael Gibson, M.S., M.D.
*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
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
Dabigatran now has a superiority labeling for stroke in the US
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Ischemic/Unspecified StrokeIschemic/Unspecified Stroke
D 110 mg vs. Warfarin
D 150 mg vs. Warfarin
RR =1.1195% CI = 0.89-1.40P = 0.35
RR = 0.7695% CI = 0.60-0.98P = 0.03
Years of Follow-up
Cu
mul
ativ
e H
azar
d R
ates
0.0
0.02
0.04
0.06
0.08
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
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Revised US LabelRevised 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)
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Dabigatran 110 mg 2.71% / yr 0.8 0.003Dabigatran 150 mg 3.11% / yr 0.93 0.31
Warfarin 3.36% / yr
150 mg Dabigatran vs 110 mg Dabigatran = HR of 1.16 (1.00–1.34) p = 0.052
Major BleedingHR
ITTP-valueRE-LY
Rivaroxaban 20 mg 3.60% / yr 0.92 0.58*
Warfarin 3.45% / yr
ROCKET
C. Michael Gibson, M.S., M.D.
*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-value
Apixaban 5 mg 2.13% / yr 0.69 <0.001
Warfarin 3.09% / 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
2 g drop in 24 hours
2 g drop
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Post Marketing SurveillancePost 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
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Post Marketing SurveillancePost 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
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All Cause MortalityAll 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
Rivaroxaban 20 mg 4.52% / yr 0.92 0.152*
Warfarin 4.91% / yr
ROCKET
RE-LY
C. Michael Gibson, M.S., M.D.
*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
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
95% CI 0.89 (0.80, 0.998)N=448 events planned, 480 in trial
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Japanese RE-LY Data: Baseline Characteristics
Characteristic Overall Japan
Randomized 18,113 326
Mean age (years) 71.5 71.2
Male (%) 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 5.5
CHF (%) 32.0 31.0
Baseline ASA (%) 39.8 35.9
VKA 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
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Region nINR <
2.0INR2.0-
3.0INR >
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
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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
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Bleeding Events in Japanese Subjects
Event (yearly rate)
110 mg bid (N=107)
150 mg bid (N=111)
Warfarin(N=108)
Major bleeding8 (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
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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
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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
-IN
R
2.5 mg
dementia
aspirin
Age 81 Female ( Living alone, ADL : independent )Chronic AF HT(-), No heart disease, DM(-), LAD 43mm
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29th 4,2005 14th 5,2005
Age 81 Female ( Living alone, ADL : independent )Chronic AF HT(-), No heart disease, DM(-), LAD 43mm )
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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
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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
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Severity of stroke by AF type
Sustained 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
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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 )
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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 RegistryCHADS2 Score of registered AF patients (n=7,937)
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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 personyears
of 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)
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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
0.320.320.230.23
0.760.76
RRR59 %
RRR70%
Eve
nt
rate
(%
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
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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
WarfarinINR2.0 to 3.0 for < 70 years oldINR1.6 to 2.6 for ≥ 70 years old
Considered
Dabigatran
WarfarinINR2.0 to 3.0 for < 70 years oldINR1.6 to 2.6 for ≥ 70 years old
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)