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TRANSCRIPT
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I DOA Sono Tutti Uguali?
Quale Farmaco Per
Quale Paziente
Gianluca Botto, MD,
FAAC, FESC
UO Elettrofisiologia
Ospedale Sant’ Anna, Como
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Presenter Disclosure Information
Research support:
Boston Scientific, Medtronic; St. Jude Medical, Bayer
Healthcare, Daijchi, Gilead, Sanofi
Advisory Board:
Biotronik, Medtronic; St. Jude Medical, MSD, Bayer
Healthcare, Boehringer, BMS, Pfizer, Sanofi
Speaker Fees:
Boston Scientific, Medtronic, St. Jude Medical, Sorin
Group, Bayer Healthcare, Boehringer, BMS, Meda,
MSD, Pfizer, Sanofi
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The Promise of NOAs
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Anticoagulation in AFWhat Was The Situation in 2009 ?
■ Treatment recommendation from 2006 ACC/AHA/ESC GLs 1
- CHADS2 score >1: VKA- CHADS2 score =1: ASA or VKA- CHADS2 score >0: ASA or nil
■ Only 50-60% of eligible pts were receiving VKA 2
■ Of those receiving VKA, average TTR was often below 50% 3
►Majority of pts were suboptimally treated
►Need for large RCTs that was representative of clinical practice
1-Fuster V. Circulation 2006; 2-Go AS. Ann Intern Med 1999; 3-Reynolds MW Chest 2004
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Desirable Qualities of a New
Anticoagulant
• Oral
• Fixed dosing
• Rapid onset and offset of action
• Predictable anticoagulant response (no monitoring)
• Minimal food and drug interactions
• As or more effective than current agents
• As or safer than current agents
• More cost-effective than current Rxs
• Reversible
7
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Mean 2,1 Mean 2,1 Mean 3,5 Mean 2,8
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XANTUS: Incident Rate of
Stroke/SE, Major Bleeding and All-Cause Death by CHA2DS2-VASc Score
174 685 1313 1578 1405 837 789 6781
CHA2DS2-VASc score
Patients (n)
Camm AJ. Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466;
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Indirect
Comparison
of NOAs in
Pts with AFA Network Meta-analisys
Harenberg J. Int Angiol 2012; 31: 330-9
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Po
inte
rs T
ow
ard
s W
hic
h N
OA
Cs
to C
ho
ose
High risk of bleedinge.g. HAS-BLED ≥3
Agent/dose with the lowest rate of bleeding
ApixabanDabigatran 110Edoxaban 30
Previous GI bleeding or high risk of GI bleed
Agent with the lowest incidence of GI bleed
Apixaban
High risk of ischemic stroke, low risk of bleeding
Agent/dose with the best reduction of ischemic stroke Dabigatran 150
Previous StrokeBest investigated agent or the greatest reduction of 2° stroke
ApixabanRivaroxaban
CAD, previous MI, high risk of ACS/MI
Agent with a positive effect in ACS Rivaroxaban
GI upset/disorders Agent/dose with no reported GI effectsApixabanRivaroxaban (J)
Patient preference Agents with OD formulation RivaroxabanEdoxaban
Cardioversion/ablation Agents tested in RCTs Rivaroxaban
Renal impairmentAgent least dependent on renal function
ApixabanRivaroxaban
Specific pt characteristics Consider … NOACs
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Efficacy
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Allocation to a NOAs significantly reduced the composite of
stroke or systemic embolic events by 19% as compared to WRF
The overall beneficial effect was mainly driven by a large
reduction in haemorrhagic stroke(RR on combined data: 0.49, 95%CI: 0.38-0.64, P
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Safety
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NOACs IntraCranial Haemorrage
Outcome
vs
Warfarin
RE-LY
Dabigatran
150 mg BID
HR
(95% CI)
ROCKET-AF
Rivaroxaban
20 mg OD
HR
(95% CI)
ARISTOTLE
Apixaban
5 mg BID
HR
(95% CI)
ENGAGE-AF
Edoxaban
60 mg OD
HR
(95% CI)
ICH 0.40
(0.27-0.60)
P
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Stroke/Thromboembolism and Intracranial Hemorrhage
in a Real-World AF Population The Complications of Atrial Fibrillation in the Bologna Area (CAFBO) Study.
Palareti G. CHEST 2014
20 pts with ICH
median age 82 ys
W 65%, ASA 30%
95% in pts > 70 yrs
85% occur with an INR in
2.0-3.0 range
45% in-H mortality
17% major deficit
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Ruff CT Lancet dec 2013 early on line pub modif
Secondary Safety Outcomes
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-Poor outcome
(30-day mortality = 48.6%)
-High cost
(30% more than ischemic stroke)
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US Department of Defense database mirrors the favourable
dabigatran profile seen in RE-LY® and FDA Medicare data
MORTALITY
Warfarin
D150 BID
DoD*1Warfarin
D150 & D75 BID
combined
EV
EN
T R
AT
E (
% P
ER
YE
AR
)
INC
IDE
NC
E R
AT
E P
ER
10
0P
ER
SO
N-Y
EA
RS
STROKEISCHAEMIC
STROKEICH
MAJOR
BLEEDINGMI
HR: 0.64
P
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Major Bleeding in Patients With NV-AF Pharmacovigilance Study of 27467 Pts Taking Rivaroxaban
■ From Jan 2013, to Mar 2014,
US- DoD electronic HC records
■ 496 MB events in 478 pts,
incidence of 2.86 per 100 person-yrs
■ MB was most commonly GI (88.5%) or ICl (7.5%)
■ 46.7% of MB pts received a transfusion,
none any type of clotting factor
■ 14 pts died during their MB hospitalization,
fatal bleeding incidence rate of 0.08 per 100 pts/y
Tamayo S. Clin. Cardiol. 2015; 38: 63-68
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Cost-Efficacy
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Anticoagulation Rx in Pts With NV-AF
Projected Costs, Cost-Efficacy and Cost-Benefit
Harrington AR. Stroke 2013 in press
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Antidote
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Po
llack
CV
et a
l. N
Eng
JM
ed
2015
ANNEXA-A / ANNEXA-R
- Apixaban
- Rivaroxaban
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I DOA Sono Tutti Uguali?
Quale Farmaco Per
Quale Paziente
Gianluca Botto, MD,
FAAC, FESC
UO Elettrofisiologia
Ospedale Sant’ Anna, Como
-
Characteristics of NOAs Comparison With Warfarin
WARFARIN DABIGATRAN RIVAROXABAN APIXABAN EDOXABAN
Target Vitamin K-dep.
clotting factors II,
VII, IX,and X
Thrombin Factor Xa Factor Xa Factor Xa
Bioavailability (%) >95 ∼6 >80 (with food) >50 >60 (85 with food)
Intake with food
recommended ?
NO NO Mandatory NO No official
recommendation
Absorption with
H2B/PPI ?
NO -12%-30% NO NO NO
Time to peak
activity (hs)
72-96 1-3 2,5-4 3-4 1-2
Half life (hs) 40 12-17 5-9 (young healty)
11-13 (elderly)
8-15 9-11
Dosing frequency OD BID OD BID OD
Interaction with
drugs
Numerous drugs
including substrates
of CYP2C9,
CYP3A4, CYP1A2
Strong P-gp
inhibitors
and inducers
Strong CYP3A4
inducers, strong
inhibitors of both
CYP3A4 and P-gp
Strong inhibitors
and inducers of
both CYP3A4 and
P-gp
Strong P-gp
inhibitors
and inducers
Interaction with
food
YES NO NO NO NO
Renal elim (%)
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Putting it All TogeteherWhat Should We Do Now in Clinical Practice ?
■ GI bleeding
■ Elderly and fragile pts
■ Effect of renal funcion
■ Perioperative management
■ Daily dosage (OD vs BID)
■ Drug Interaction
■ ACS/MI
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NOAs in Clinical PracticeIdentifyng Pts with Increased Bleeding Risk
■ Patient-related factors
- advanced age (≥80 ys)
- low body weight (≤60 Kg)
- renal impairment / fluctuation in renal function
- GI-related comorbidities
■ Clinical Considerations
- examine creatinine clearance rates
(not just serum creatinine)
- use of antiplatelet Rx
EHRA Practical GL. Europace 2013; 15: 625-651
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NOACs Bleeding
Outcome
vs
Warfarin
RE-LY
Dabigatran
150 mg BID
HR
(95% CI)
ROCKET-AF
Rivaroxaban
20 mg OD
HR
(95% CI)
ARISTOTLE
Apixaban
5 mg BID
HR
(95% CI)
ENGAGE-AF
Edoxaban
60 mg OD
HR
(95% CI)
GI
Bleeding
1.50
(1.19-1.89)
1.39
(1.19-1.61)
0.89
(0.70-1.15)
1.23
(1.02-1.50)
Major
Bleeding
0.93
(0.81-1-07)
1.04
(0.90-1.20)
0.69
(0.60-0.80)
1.23
(0.71-0.91)
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Dabigatran in
“Real-World”
Pts With AFData From The
DANISH Registry
■ 2:1 PS Analysis
■ D 4978
■ W 8936
Larsen TB.
JACC 2013; 61: 2264-73
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Comparison of Main Outcomes:
XANTUS versus ROCKET AF
CHADS2 Prior stroke#
ROCKET AF1 3.5 55%
XANTUS2 2.0 19%
#Includes prior stroke, SE or TIA; *Events per 100 patient-years
1. Patel MR et al, N Engl J Med 2011;365:883–891; 2. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466
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Apr 2012
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Clin Pharmacokinet 2010; 49: 259-68.
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Apr 2012
Noacs In Renal Dysfunction Approved European Labels And Dosing In CKD
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Apr 2012
NOACs Cessation Before Planned Surgery
EHRA Practical GL. Europace 2013; 15: 625-651
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Dosing Considerations Update Under Review
Courtesy of H. Heidbuchel and J. Camm
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Patients’
Preferences For
Type 2 Diabetes
Treatment Dosing
Schedules
Hauber AB.
Patient Preference and Adherence
2013:7 937–949
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Coleman CI. Curr Med Res Opin 2012; 28: 669-680
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Daily Dosing Frequency and Adherence Among NVAF Pts
26% higher likelihood
of adherence with OD
dosing regimen
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1. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466; 2. Piccini JP et al, Eur Heart J 2014; 35(28):1873-80;
3. Beyer-Westendorf J et al, Blood 2014; 124(6):955-62
XANTUS: Treatment Persistence and Patient Satisfaction
Persistence with rivaroxaban in XANTUS was 80% at 1 year
Over 75% of patients were ‘very satisfied/satisfied’ with their
treatment
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Nonadherence to a NOAC is
Associate to Worse Outcomes
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Bleeding Risk With EdoxabanOnce-daily vd Twice-daily Dosing
Edoxaban dose and regimens
Ble
edin
g incid
ence (
%)
Weitz JI. Thromb Haemost 2010; 104: 633-641
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Rivaroxaban Dosing
Overlap B/ween od and bid Regimens• The Cmax and Ctrough of rivaroxaban increased in a dose-dependent manner with both dosing
regimens up to 20 mg (total daily doses).
• The 90% intervals for Cmax and Ctrough overlapped between the two dosing regimens.
100
200
300
400
05 10 15 20
Rivaroxaban daily dose (mg)
Riv
aro
xa
ba
n C
max
(μg
/l)
bid
od
5 10 15 20
120
100
80
60
40
20
0
Rivaroxaban daily dose (mg)
Riv
aro
xa
ba
n C
thro
ug
h(μ
g/l
)
bid
odCmax Cthrough
Mueck W. Thromb Haemost 2008;100:453–461
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Novel Oral Anticoagulants
NOAs all provide important advantage over W, including convenience, at least as effective preventionof stroke, and less intracranial hemorrhage
Until head-to-head trials or large scale observationalstudies that reflects routine use of these agents are available, indirect comparison are just one tool for hypothesis generating
Growing clinical practice data, despite differences in selection, treatment and management of pts, supportthe efficacy and safety profile of NOACs