Come Orientare La Scelta Dei Nuovi Anticoagulanti Orali

Fibrillazione Atriale
Non Valvolare:
Come Orientare La
Scelta Dei Nuovi
Anticoagulanti Orali
Gianluca Botto, MD, FAAC, FESC
Divisione di Cardiologia
Ospedale Sant’ Anna, Como
The
The Promise
Promise of
of NOAs
Antithrombotic Treatments in
non valvular AF (4.845 pts)
OAC
Other ATT
None
Courtesy of Di Pasquale G.
5
Desirable
Desirable Qualities
Qualities of
of aa New
New
Anticoagulant
Anticoagulant
•
•
•
•
Oral
Fixed dosing
Rapid onset and offset of action
Predictable anticoagulant response
(no monitoring)
•
•
•
•
•
Minimal food and drug interactions
Reversible
As or more effective than current agents
As or safer than current agents
More cost-effective than current Rxs
Efficacy
Efficacy
Trials
Trials on
on New
New Oral
Oral Anticoagulants
Anticoagulants in
in AFIB
AFIB
Trial
Company
Dose
Design
Dabigatran
Boeringer
110 mg and
150 mg bid
PROBE
ROCKET-AF
Rivaroxaban
Bayer
20 mg daily
double-dummy,
double-blind
ARISTOTLE
Apixaban
Bristol MS / Pfizer
5 mg bid
double-dummy,
double-blind
ENGAGE-AF
Edoxaban
Daiichi Sankyo
30 mg and
60 mg daily
double-dummy,
double-blind
Betrixaban
Merck
40,60,80
mg daily
double-blind,
open label W
YM150
Astrellas
six
regimens
double-blind,
open label W
RE-LY
EXPLORE-Xa
OPAL-2
Drug
NOAs
NOAs vs
vs Warfarin
Warfarin in
in Pts
Pts with
with AF
AF
ALL-CAUSE STROKE or SE
ISCHEMIC STROKE
HEMORRHAGIC STROKE
Miller CS. Am J Cardiol 2012; 110: 453-460
Recent
Recent NOA
NOA Trials:
Trials: Ischemic
Ischemic Stroke
Stroke
RELY
Dabigatran 110 mg
Dabigatran 150 mg
Warfarin
ROCKET
Rivaroxaban 20 mg
Warfarin
ARISTOTLE
Apixaban 5 mg
Warfarin
1.34% / yr
0.92% / yr
HR
1.20
0.76
P-value (ITT)
0.35
0.03
1.20% / yr
1.62% / yr
0.99
0.92
0.92
0.42
1.64% / yr
0.97% / yr
1.05% / yr
Patel MR. N Engl J Med 2011; Connolly SJ. N Engl J Med 2009; Granger C. N Eng J Med 2011
Efficacy
Efficacy and
and TTR
TTR in
in 33 SPAF
SPAF Studies
Studies
Safety
Safety
NOAs
NOAs vs
vs Warfarin
Warfarin in
in Pts
Pts with
with AF
AF
MAJOR BLEEDING
INTRACRANIAL BLEEDING
GE BLEEDING
Miller CS. Am J Cardiol 2012; 110: 453-460
Indirect
Indirect
Comparison
Comparison of
of
NOAs
NOAs in
in
Pts
Pts with
with AF
AF
A
A Network
Network Meta-analisys
Meta-analisys
Harenberg J. Int Angiol 2012; 31: 330-9
Net
Net Clinical
Clinical Benefit
Benefit for
for Warfarin
Warfarin and
and NOAs
NOAs
by
by CHA
CHA22DS
DS22-VASc
-VASc Score
Score
Banerjee A. Thrombosis Haemost 2012
Cost-Efficacy
Cost-Efficacy
Anticoagulation
Anticoagulation Rx
Rx in
in Pts
Pts With
With NV-AF
NV-AF
Projected
Projected Costs,
Costs, Cost-Efficacy
Cost-Efficacy and
and Cost-Benefit
Cost-Benefit
Harrington AR. Stroke 2013 in press
Who
Who is
is NOT
NOT aa Candidate
Candidate For
For NOAs
NOAs ??
Mechanical valve
Creat-Cl < 30 ml/min
Severe hepatic dysfunction
Non-compliant with W
Fibrillazione Atriale
Non Valvolare:
Come Orientare La
Scelta Dei Nuovi
Anticoagulanti Orali
Gianluca Botto, MD, FAAC, FESC
Divisione di Cardiologia
Ospedale Sant’ Anna, Como
Putting
Putting itit All
All Togeteher
Togeteher
What
What Should
Should We
We Do
Do Now
Now in
in Clinical
Clinical Practice
Practice ??
■
■
■
■
■
■
■
Daily dosage (OD vs BID)
Effect of renal funcion
Perioperative managem
Drug Interaction
Elderly and fragile pts
ACS/MI
GI bleeding
Patients’
Patients’
Preferences
Preferences For
For
Type
Type 22 Diabetes
Diabetes
Treatment
Treatment Dosing
Dosing
Schedules
Schedules
Hauber AB.
Patient Preference and Adherence
2013:7 937–949
Summary
Summary Of
Of The
The RCTs
RCTs Involving
Involving Novel
Novel Anticoagulants
Anticoagulants vs
vs
Warfarin
Warfarin For
For Stroke
Stroke Prevention
Prevention In
In Non-Valvular
Non-Valvular AF
AF
Apr 2012
Anticoagulants: PK Parameters
AVK
a-IIa
a-Xa
Poulsen BK et al, Drugs 2011
Clin Pharmacokinet 2010; 49: 259-68.
Time
Time Course
Course of
of Effect
Effect of
of Dabigatran
Dabigatran on
on aPTT
aPTT
Weitz JI. Circulation 2012; 126: 2428-2432
Renal
disease
Hepatic
disease
Kreutz R, Fundamental Clin Pharmacol 2011
Estimated Drug Half-lives And Effect On
AUC NOA Plasma Concentrations
@ Different Stages Of CKD Compared To Healthy
Controls
Apr 2012
Noacs In Renal Dysfunction
Approved European Labels And Dosing In CKD
Apr 2012
NOAs
Last Intake Of Drug Before
Elective Surgical Intervention
Apr 2012
Effect on NOAs plasma
levels
(area under the curve, AUC)
from drug–drug
interactions and clinical
factors.
Recommendations
towards NOAC dosing
EHRA Practical Guidelines
Europace 2013;
15: 625-651
Dabigatran Etexilate And Dronedarone
Effect of dronedarone (P-gp inhibitor) on pharmacokinetics and
pharmacodynamics of dabigatran was studied1
– Sponsored by sanofi-aventis
Dronedarone 400 mg BID increased steady-state dabigatran
exposures by 1.7- to 2.0-fold1
– Due to increased absorption through P-gp inhibition
– Similar level of interaction to that observed for dabigatran in the
presence of other P-gp inhibitors, such as amiodarone and verapamil
No effect of dronedarone on renal clearance of dabigatran1
EU SmPC: co-administration of dabigatran and dronedarone
not recommended because inadequate clinical data are
available (Pradaxa®: EU SmPC, 2012)
1. Brunet A. Eur Heart J 2011; 32: 618–9
Circulation. 2012; 125: 669-676
ATLAS ACS 2 TIMI 51
N=15,526*
Physician's decision to add thienopyridine or not
Stratum
Stratum 1:
1: ASA
ASA
alone
alone (7%)
(7%)
Placebo
Placebo
n=355
n=355
Rivaroxaban
Rivaroxaban
2.5
2.5 mg
mg bid
bid
n=349
n=349
Stratum
Stratum 2:
2: ASA
ASA ++
thienopyridine
thienopyridine (93%)
(93%)
ASA dose =
75–100 mg/day
Rivaroxaban
Rivaroxaban
55 mg
mg bid
bid
n=349
n=349
Placebo
Placebo
n=4821
n=4821
Rivaroxaban
Rivaroxaban
2.5
2.5 mg
mg bid
bid
n=4825
n=4825
Event-driven study – 1002 events
*184 patients were excluded from the efficacy analyses prior to unblinding because of trial misconduct
at three sites
Mega JL et al. N Engl J Med 2011. 13 November 2011
Rivaroxaban
Rivaroxaban
55 mg
mg bid
bid
n=4827
n=4827
NEJMed 2013
RE-LY
RE-LY Cardioversion
Cardioversion Subgroup
Subgroup
Stroke/systemic embolism (%)
Stroke
Stroke or
or Systemic
Systemic Embolism
Embolism with/without
with/without TEE
TEE
2.5
With TEE prior to cardioversion
(24.8% of pts)
Without TEE prior to cardioversion
(13.3% of pts)
2.0
P=0.65
1.5
P=0.54
P=0.17
1.14
1.0
P=0.75
0.83
0.5
0.61
0.39
0.0
0.0
Dabigatran
110 mg BID
Dabigatran
150 mg BID
Warfarin
Dabigatran
110 mg BID
Dabigatran
150 mg BID
0.52
Warfarin
Similar rates of stroke or systemic embolism with/without TEE before cardioversion
Nagarakanti R. Circulation 2011;123:131–6
Kirchhof P. EHRA-Europace Meeting, Athens 2013
Apr 2012
NOAs Global Market Share
June 2013
RIVAROXABAN
DABIGATRAN
APIXABAN
IMS MIDAS Database Monthly Sales
“Humanity greatest advance are not
in its discoveries,…
… but in how those
discoveries are applied”
Bill Gates, June 7, 2007
Harvard Commencement Address
Novel
Novel Oral
Oral Anticoagulants
Anticoagulants
NOAs all provide important advantage over W,
including convenience, at least as effective prevention
of stroke, and less intracranial hemorrhage
Until head-to-head trials or large scale observational
studies that reflects routine use of these agents are
available, indirect comparison are just one tool for
hypothesis generating
The new agents provide an important opportunity to
improve the care of pts with AFIB including for pts
with indications but not currently treated with any
OAC.