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2016-2017
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October 7–8
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December 14–16
Mexico City, Mexico
Heart House
Washington, DC
New York Hilton
New York
Heart House
Washington, DC
ACC Latin America Conference
2016
How to Become a
Cardiovascular Investigator
New York Cardiovascular
Symposium
Teaching Skills Workshop for
Emerging Faculty
October 8
Kentucky Chapter Annual
Meeting 2016
Lexington Convention Center
® (dabigatran etexilate mesylate)
Pradaxa
Lexington
, KY
Pradaxa
Table 2 (Cont'd) patients to immediately report if they experience any of the above signs
patients to immediately report if they experience
any of theetexilate
above signsmesylate)
® (dabigatran
or symptoms.
of spinal hematoma are suspected,
or symptoms. If signs or symptoms of spinal hematoma are suspected, Event
PRADAXAIf signs or symptoms PRADAXA
capsules,
for
oral
use
Warfarin
initiate150
urgent
including
initiate urgent diagnosis and treatment including consideration for spinal
150
mg consideration for spinal
mg diagnosis and treatment
N even
= 5998
cordNdecompression
though
such
treatment may not prevent or
cord decompression BRIEF
even though
such treatment
may not preventINFORMATION
or
SUMMARY
OF PRESCRIBING
vs. Warfarin
= 6059
b
n (%/year
)
b
reverse
neurological
sequelae.
Thromboembolic
and Bleeding
reverse
neurological
sequelae.
Thromboembolic
and
Bleeding
)
HR
(95%
CI)
n
(%/year
Please see package insert for full Prescribing Information.
Please see package insert for full Prescribing Information.
Events in Patients with Prosthetic Heart Valves: The safety and
Events in Patients with Prosthetic Heart Valves: The safety and
Hemorrhagic
6 (0.06)
40 in
(0.37)
0.16
efficacy
of
PRADAXA
patients
with
bileaflet
mechanical
prosthetic
efficacy
of
PRADAXA
in
patients
with
bileaflet
mechanical
prosthetic
October
15
WARNING: (A) PREMATURE DISCONTINUATION
WARNING:
(A) PREMATURE
DISCONTINUATION
Strokee
0.37) trial, in which patients
heart valves was evaluated in the(0.07,
RE-ALIGN
heart valves was evaluated in theOF
RE-ALIGN
trial,
in which patients
PRADAXA
INCREASES
THE RISK OF
OF PRADAXA INCREASES THE RISK OF
(0.17)mechanical
46 (0.43)
0.38valves (recently implanted or
with 17
bileaflet
prosthetic heart
with bileaflet mechanical prosthetic heart valves
(recently implanted
THROMBOTIC
EVENTS,or Other ICH
THROMBOTIC EVENTS,
(0.22,to0.67)
implanted more than three months prior
enrollment) were randomized
implanted more than three months prior
enrollment) were randomized
(B)toSPINAL/EPIDURAL
HEMATOMA
(B) SPINAL/EPIDURAL HEMATOMA
adjusted
warfarin
or
150,
220,
or 300 mg of PRADAXA twice a
to dose adjusted warfarin or 150, 220, or 300 mg of PRADAXA twice a Gastrointestinal to dose
162 (1.59)
111 (1.05)
1.51
(A)
PREMATURE
DISCONTINUATION
OF
PRADAXA
(A) PREMATURE DISCONTINUATION OF PRADAXA
day. RE-ALIGN was terminated early(1.19,
due to1.92)
the occurrence of significantly
day. RE-ALIGN was terminated early due to the occurrence of significantly
THEthrombosis,
RISK OF THROMBOTIC
EVENTS
INCREASES THE RISK OF THROMBOTIC EVENTS
more thromboembolic events (valve thrombosis, stroke, transient
more thromboembolic INCREASES
events (valve
stroke, transient
Columbus
Hotel
Easton
f
Prematureinfarction)
discontinuation
any oral
Premature
discontinuation
of anyatoral
anticoagulant,
7 (0.07)
16 myocardial
(0.15)
0.45 and an excess of major
ischemic
attack, and
infarction)
ischemic attack, and myocardial
and anofexcess
of anticoagulant,
major Fatal Bleeding
PRADAXA,
increases
the risk
of thrombotic
including PRADAXA, increases the risk of thrombotic
(0.19, pericardial
1.10)
bleeding (predominantly post-operative
effusions requiring
bleeding (predominantlyincluding
post-operative
pericardial
effusions
requiring
events. If anticoagulation with PRADAXA is discontinued
events. IfColumbus,
anticoagulationOH
with PRADAXA is discontinued
intervention
intervention for hemodynamic
compromise)
in thepathological
PRADAXA treatment
3 (0.03)for hemodynamic
9 (0.08) compromise)
0.35 in the PRADAXA treatment
for a reason
other than
bleeding orICH
completion
for a reason other than pathological bleeding or completion
(0.09,
1.28)
arm
as
compared
to
the
warfarin
treatment
arm.
These
bleeding and
arm
as
compared
to
the
warfarin
treatment
arm.
These
bleeding
and
of a course of therapy, consider coverage with another
of a course of therapy, consider coverage with another
were seen both0.59
in patients who were initiated on
thromboembolic events anticoagulant
were seen both [see
in patients
who were
initiated on Non-intracranialg thromboembolic
4 (0.04) events
7 (0.07)
Warnings
and Precautions].
anticoagulant [see Warnings and Precautions].
PRADAXA post-operatively within three
days
of mechanical bileaflet valve
PRADAXA post-operatively within three days of mechanical bileaflet valve
(0.17,
2.02)
HEMATOMA
(B) SPINAL/EPIDURAL HEMATOMA
implantation, as well as in patients whose valves had been implanted
implantation, as well as(B)
in SPINAL/EPIDURAL
patients whose valves
had been implanted a
Patients during
treatment
or within
days of
stopping
studytotreatment.
MajorTherefore, the use of
Epidural
or spinal
hematomas
may
in patients
treated
Epidural or
spinal hematomas
October
20–22may occur in patients treated more than three months
more
than 2three
months
prior
enrollment.
prior to
enrollment.
Therefore,
theoccur
use of
bleeding events
each subcategory were counted once per patient, but
with PRADAXA
who
aremechanical
receiving neuraxial
or within PRADAXA
with PRADAXA who are receiving neuraxial anesthesia or
is contraindicated in patients with mechanical prosthetic
PRADAXA is contraindicated
in patients
with
prosthetic anesthesia
patients
have contributed events to multiple subcategories.
undergoing
spinal
puncture.
hematomas
maymay
result
undergoing spinal puncture. These hematomas may result
valves
[see Contraindications]. The use of PRADAXA for the prophylaxis
valves [see Contraindications].
The use
of PRADAXA
forThese
the prophylaxis
b
Annual
100 pt-years = 100 * number of subjects with event/
in long-term
or permanent
paralysis.
Consider
theseevent
risksrate per of
in long-term or permanent paralysis. Consider these risks
thromboembolic events in patients with atrial fibrillation in the setting
of thromboembolic events
in patients with
atrial fibrillation
in the setting
subject-years.
when scheduling patients for spinal procedures.
Factors Subject-years is defined as cumulative number of days from
when scheduling patients for spinal procedures. Factors
of other
valvular
including
of other forms of valvular
disease, including
thedeveloping
presence ofepidural
a first drug
intake to event
date,forms
date ofof last
drug heart
intake disease,
+ 2, death
date the presence of a
thatheart
can increase
the risk of
or spinal
that can increase the risk of developing epidural or spinal
bioprosthetic
heart valve,
has not
beenbystudied
bioprosthetic heart valve,hematomas
has not beeninstudied
is not include:
recommended. (whatever occurred first)
across all treated
subjects
divided
365.25.and
In is not recommended.
these and
patients
hematomas in these patients include:
Effect
of
P-gp
Inducers
and
Inhibitors
on
Dabigatran Exposure:
Effect
of
P-gp
Inducers
and
Inhibitors
on
Dabigatran
Exposure:
case of recurrent events of the same category, the first event was considered.
• use of indwelling epidural catheters
• use of indwelling epidural catheters
c
concomitant
use or
of PRADAXA
with
P-gp inducers
(e.g., rifampin)
The concomitant use of• PRADAXA
with P-gp
inducers
(e.g., rifampin)
Defined
as bleeding The
accompanied
by one
more of the
following:
a
concomitant
use of
other drugs
that affect
hemostasis,
• concomitant use of other drugs that affect hemostasis,
reduces
to dabigatran
shouldunits
generally
be avoided. P-gp
reduces exposure to dabigatran
should generallyantibe avoided. P-gp decrease in hemoglobin
of ≥2 exposure
g/dL, a transfusion
of 2and
or more
of
suchand
as non-steroidal
such as non-steroidal antiinhibition
and
impaired
renal
function
are
the
major
independent
factors
inhibition
and
impaired
renal
function
are
the
major
independent
factors
inflammatory drugs (NSAIDs), platelet packed red blood cells, bleeding at a critical site or with fatal outcome.
inflammatory
drugs
(NSAIDs),
Radisson
Blu
Aquaplatelet
Hotel
that intracerebral
result in increased
exposure
dabigatran. Concomitant use of
that result in increased exposure
to dabigatran.
Concomitant use of dIntracranial bleed included
(hemorrhagic
stroke),tosubarachnoid,
inhibitors,
other anticoagulants
inhibitors, other anticoagulants
P-gp inhibitors in patients
renal impairment
is expected
to produce
andorsubdural
• with
a history
of traumatic
or repeated
epidural
spinalbleeds. P-gp inhibitors in patients with renal impairment is expected to produce
• a history
of traumatic
Chicago,
IL or repeated epidural or spinal
of dabigatran
increased exposure of dabigatran
compared to that seen with either factor eOn-treatment analysisincreased
based onexposure
the safety
population,compared
compared totothat
ITTseen with either factor
punctures
punctures
alone. 14
Reduction
of Risk of Stroke and Systemic Embolism in Nonalone. Reduction of Risk
Stroke and
Systemic
Embolism
in Nonanalysis presented in Section
Clinical Studies.
• ofa history
of spinal
deformity
or spinal
surgery
• a history of spinal deformity or spinal surgery
f
valvular
the dose
of PRADAXA to 75 mg twice
dose ofbetween
PRADAXAthe
to administration
75 mg twice Fatal
bleed: Adjudicated
majorAtrial
bleedFibrillation:
as definedReduce
above with
investigator
• Reduce
optimalthetiming
of PRADAXA
• optimal timing between the administration of PRADAXA valvular Atrial Fibrillation:
reported
fatal outcome
andwhen
adjudicated
deathorwith
primary
cause fromis coadministered with
daily
dronedarone
systemic
ketoconazole
daily when dronedarone or systemic
ketoconazole
is coadministered
with [see
and neuraxial
procedures
is not known
Warnings
and neuraxial procedures is not known [see Warnings
PRADAXA in patients with moderate renal impairment (CrCl 30-50 mL/
PRADAXA in patients with moderate
renal impairment (CrCl 30-50 mL/ bleeding.
and Precautions].
and Precautions].
g
Non-intracranial
fatal min).
bleed:Avoid
Adjudicated
bleedand
as defined
above andin patients with severe
use of major
PRADAXA
P-gp inhibitors
min). Avoid use of PRADAXA
andpatients
P-gp inhibitors
in patients
with severe
October
21–22
Monitor
frequently
for signs
and symptoms
of
Monitor patients
frequently
for signs and symptoms of
adjudicated is
death with renal
primaryimpairment
cause from (CrCl
bleeding
but without
symptomatic
15-30
mL/min)
[see Drug Interactions and
renal impairment (CrClneurological
15-30 mL/min)
[see DrugIf Interactions
impairment.
neurologicaland
compromise
neurological impairment. If neurological compromise is
intracranialand
bleed basedUse
on in
investigator’s
clinical assessment.
Specific Populations].
Treatment and Reduction in the Risk of
Use in Specific Populations].
and Reduction
in the Risk
noted,Treatment
urgent treatment
is necessary
[seeofWarnings
noted, urgent treatment is necessary [see Warnings and
Deep Venous Thrombosis
and Pulmonary Embolism:
Recurrence of Deep Venous
Thrombosis and Pulmonary Embolism: There was a higherRecurrence
Precautions].
Precautions].
rate of anyofgastrointestinal
bleeds in patients
Avoidmg
usethan
of PRADAXA
concomitant
P-gp
inhibitors in patients with
Avoid use of PRADAXA Consider
and concomitant
P-gp inhibitors
in patients
with receiving PRADAXA 150
in patientsand
receiving
warfarin
(6.6%
the benefits
and risks
before neuraxial
Consider the benefits and risks before neuraxial
CrCl
<50
mL/min
[see
Drug
Interactions].
CrCl
<50
mL/min
[see
Drug
Interactions].
vs.
4.2%,
respectively).
The
risk
of
major
bleeds
was
similar
with
intervention in patients anticoagulated or to be
intervention in patients anticoagulated or to be
Grand[see
Traverse
warfarinREACTIONS:
across majorThe
subgroups
anticoagulated
[see Warnings
Precautions].
anticoagulated
WarningsResort
and Precautions].
ADVERSE
followingdefined
seriousbyadverse reactions are
ADVERSE REACTIONS:
The following serious
adverse and
reactions
are PRADAXA 150 mg and
(see Figure
1, below),
with theIncreased
exceptionRisk
of of Thrombotic Events
described
elsewhere
in the labeling:
described elsewhere in the labeling: Increased Risk of Thrombotic Events baseline characteristics
Traverse
City,Reduction
MI
INDICATIONS
AND
USAGE:
Reduction
of
Risk
of
Stroke
and
INDICATIONS
AND USAGE:
of Risk of Stroke and after Premature Discontinuation
age,
where
there
was
a
trend
towards
a
higher
incidence
of major
after Premature Discontinuation [see Warnings
and Precautions]; Risk
[see Warnings and Precautions]; Risk
Systemic
Embolism inSpinal/Epidural
Non-valvularAnesthesia
Atrial Fibrillation:
Systemic Embolism in Non-valvular Atrial Fibrillation: PRADAXA of Bleeding [see Warnings
bleeding PRADAXA
on PRADAXA
(hazard [see
ratioWarnings
1.2, 95%
1.0 to 1.5)Spinal/Epidural
for
of Bleeding
andCI:
Precautions];
Anesthesia
and Precautions];
is indicated
reduce the Thromboembolic
risk of stroke andand
systemic
in orofPuncture
is indicated to reduce the risk of stroke and systemic embolism in or Puncture [see Warnings
patientsembolism
≥75 years
age. Gastrointestinal
Reactions:Thromboembolic and
[see Warnings Adverse
and Precautions];
and toPrecautions];
patientswith
withProsthetic
non-valvular
atrial
fibrillation.
Treatment
of
Deep
Venous
patients with non-valvular atrial fibrillation. Treatment of Deep Venous Bleeding Events in Patients
150 Events
mg had
an increased
incidence
Bleeding
in Patients
with Prosthetic
HeartofValves [see Warnings
Heart Valves [see Warnings Patients on PRADAXA
Thrombosis
andadverse
Pulmonary
Embolism:
is indicated adverse
for and reactions
Thrombosis and Pulmonary Embolism: PRADAXA is indicated fo r and Precautions]. The
(35%The
vs. most
24% on
warfarin).
These
Precautions].
serious
adverse
reactions reported with
most serious
reactions
reported PRADAXA
with gastrointestinal
thetotreatment
of
deep
venous and
thrombosis
and pulmonary
embolism
the treatment of deep venous thrombosis and pulmonary embolism PRADAXA were related
were commonly
dyspepsia
(including
abdominal
pain upper,
abdominal
PRADAXA
were
related
to
bleeding
[see
Warnings
and Precautions].
bleeding
[see
Warnings
Precautions].
October
in patients
who
have
been
treated
with
a
parenteral
anticoagulant
for
in patients who
have been21–22
treated with a parenteral anticoagulant for Clinical Trials Experience:
epigastric
discomfort)
gastritisClinical and
Trials
Experience:
Becauseand
clinical
trials are conducted under
Because clinical trials are conducted under pain, abdominal discomfort,
5-10adverse
days. Reduction
in the
Risk of
Recurrence
of symptoms
Deep Venous
5-10 days. Reduction in the Risk of Recurrence of Deep Venous widely varying conditions,
(including
erosive gastritis,
widelyGERD,
varyingesophagitis,
conditions, adverse
reactions gastric
rates observed in the clinical
reactions rates
observed
in the
clinical like
and Pulmonary
PRADAXA
is indicated
to trials ofgastritis,
Thrombosis and Pulmonary Embolism: PRADAXA is indicated to trials of a drug cannotThrombosis
hemorrhage,
hemorrhagic
hemorrhagic
erosive
gastritis,toand
a drug cannot
be directly
compared
rates in the clinical trials
be directly compared
to rates inEmbolism:
the clinical trials
thereflect
risk of recurrence
of deep venous
thrombosis
and pulmonary
reduce the risk of recurrence of deep venous thrombosis and pulmonary of another drug and reduce
gastrointestinal
ulcer).ofHypersensitivity
Reactions:
the RE-LY
study,observed in practice.
another drug and
may notInreflect
the rates
may not
the rates observed
in practice.
in patients
have been
previously treated.
embolism in patients who have been previously treated.
drug hypersensitivityReduction
(including ofurticaria,
Risk of rash,
Strokeand
andpruritus),
Systemicallergic
Embolism in Non-valvular
Reduction of Risk of embolism
Stroke and
Systemicwho
Embolism
in Non-valvular
anaphylactic
reaction,
and anaphylactic
shock(Randomized
were reportedEvaluation
in
Fibrillation:
The RE-LY
of Long-term
RE-LY (Randomized Evaluation
Long-term edema,
CONTRAINDICATIONS:
PRADAXA isof contraindicated
in patients
with: Atrial
CONTRAINDICATIONS:
PRADAXA
is contraindicated
in patients with: Atrial Fibrillation: The
Chase Park
Plaza
Hotel
of patients
PRADAXA.
Treatment
and Reduction
in
Anticoagulant
Therapy)
study provided
safety information
on the use of
studypathological
provided safety
information
the use and
of <0.1%
Active
bleeding
[see on
Warnings
Precautions
and receiving
Active pathological bleeding [see Warnings and Precautions and Anticoagulant Therapy)
the
Risk
of
Recurrence
of
Deep
Venous
Thrombosis
and
Pulmonary
two
doses
of
PRADAXA
and
warfarin.
The
numbers
of
patients
and their
two
doses
of
PRADAXA
and
warfarin.
The
numbers
of
patients
and
their
Adverse
Reactions];
History
a
serious
hypersensitivity
reaction
to
Adverse Reactions];
History
of
a
serious
hypersensitivity
reaction
to
St. Louis, MO
was studied
in 4387in patients
in 4 pivotal,
are described
Table 1. Limited
information is presented on
in Table(e.g.,
1. Limited
information
is presented
on Embolism:
PRADAXA
anaphylactic
reaction
or anaphylactic
shock)PRADAXA
[see exposures
PRADAXA (e.g., anaphylactic reaction or anaphylactic shock) [see exposures are described
parallel,
double-blind
trials.arm
Three
of these
trialsis not
wereapproved.
110 mg dosing
because
this dose
because
this dose isMechanical
not approved.
Adverse
Reactions];
prosthetic heart valve
[see randomized,
Warnings the
Adverse Reactions]; Mechanical prosthetic heart valve [see Warnings the 110 mg dosing arm
active-controlled (warfarin) (RE-COVER, RE-COVER II, and RE-MEDY),
and Precautions].
and Precautions].
Table 1 was
Summary
of Treatment
Exposure
in RE-LY
Table 1 Summary of Treatment Exposure in RE-LY
and
one
study
(RE-SONATE)
placebo-controlled.
The
demographic
WARNINGS AND PRECAUTIONS: Increased Risk of Thrombotic
WARNINGS AND PRECAUTIONS: Increased Risk of Thrombotic
characteristics
were similar among the 4 pivotal studies
and between
PRADAXA
PRADAXA
PRADAXA
PRADAXA
Events after
Premature
Discontinuation: Premature
discontinuation
Events after Premature Discontinuation: Premature discontinuation
Octoberincluding
28–30
the treatment
groups within these studies. Approximately
of mg
mg
150 mg PRADAXA,
Warfarin
110 mg 60%150
Warfarin
of any oral110
anticoagulant,
including
in the absence
of adequate
of any oral anticoagulant,
PRADAXA, in the absence of adequate
twice
daily twiceincreases
daily the risk of thrombotic
dailyyears.twice
the treatedevents.
patients
of 55.1
The daily
alternative
anticoagulation
If were male, with a mean agetwice
alternative anticoagulation increases the risk of thrombotic events. If
majority ofbleeding
the patients were white (87.7%), 10.3% were Asian, and
discontinued 6059
for a reason other
than
pathological
PRADAXA is discontinued for a reason other than pathological bleeding Total number treated PRADAXA is5983
5998
number treated
6059
5998
1.9% were
black withTotal
a mean
CrCl of 105.6 mL/min.5983
Bleeding events
or completion of a course of therapy, consider coverage
with another
or completion of a course of therapy, consider coverage with another
for the appropriate.
4 pivotal studies
were classified as major bleeding events if at
Exposure
anticoagulant and restart PRADAXA as soon as medically
anticoagulant and restart PRADAXA as soon as medically appropriate. Exposure
one ofand
thecan
following criteria applied: fatal bleeding, symptomatic
Risk of Bleeding:
PRADAXA
the risk ofleast
bleeding
Risk of Bleeding: PRADAXA increases the risk of bleeding and can
> 12 months
4936
4939increases5193
12 organ
months(intraocular, intracranial,
4936 intraspinal
4939
5193
Jeddah, Saudi Arabia
a critical area> or
cause significant and, sometimes, fatal bleeding. bleeding
Promptlyinevaluate
cause sign ificant and, sometimes, fatal bleeding. Promptly evaluate
or
intramuscular
with
any signs or2387
symptoms of 2405
blood loss (e.g.,
a drop in hemoglobin and/or compartment
any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or
> 24 months
2470
> 24 monthssyndrome, retroperitoneal
2387 bleeding,
2405
2470
bleeding, or pericardial bleeding), bleeding causing a fall
hematocrit or hypotension). Discontinue PRADAXA in intra-articular
patients with active
hematocrit or hypotension). Discontinue PRADAXA in patients with active
in hemoglobin
level ofMean
2.0 exposure
g/dL (1.24
mmol/L or more,
to
21.3 include
(months)
20.5or leading 20.3
21.3
pathological20.5
bleeding. Risk20.3
factors for bleeding
the concomitant
pathological bleeding. Risk factors for bleeding include the concomitant Mean exposure (months)
of 2 or more units of whole blood or red cells). RE-COVER
drugs that increase
of bleedingtransfusion
(e.g., anti-platelet
use of other drugs that increase the risk of bleeding (e.g., anti-platelet Total patient-years use of other
10,242
10,261 the risk
10,659
Totalcompared
patient-years
10,242
10,261
10,659
and
RE-COVER
II
studies
PRADAXA
150
mg
twice
daily
and
agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs).
agents, heparin,
fibrinolytic therapy,
and chronic use of NSAIDs).
November
18–20
warfarin inforpatients
the treatment of deep vein thrombosis and pulmonary
anticoagulant
activity
and half-life
PRADAXA’s anticoagulant activity and half-life are increased in patients Drug DiscontinuationPRADAXA’s
in RE-LY: The
rates of adverse
reactions
leadingareto increased
Drug
Discontinuation
The ratesparenteral
of adverse reactions leading to
embolism.
received
5-10 days in
of RE-LY:
an approved
with were
renal21%
impairment.
Reversal
of and
Anticoagulant
Effect: A Patients
specific treatment
with renal impairment. Reversal of Anticoagulant Effect: A specific treatment discontinuation
for PRADAXA
150 mg
16% for anticoagulant
discontinuation
21%
for PRADAXA
therapy followed by
6 months, withwere
mean
exposure
of 164 150 mg and 16% for
reversaladverse
agent reactions
(idarucizumab)
fortodabigatran
is available when reversal
reversal agent (idarucizumab) for dabigatran is available when reversal warfarin. The most frequent
leading
discontinuation
warfarin.
The
most
frequent
adverse
reactions
leading to discontinuation
days,Forof emergency
oral only treatment; warfarin was overlapped with parenteral
of the and
anticoagulant
effectevents
of dabigatran
is needed:
of the anticoagulant effect of dabigatran is needed: For emergency of PRADAXA were bleeding
gastrointestinal
(i.e., dyspepsia,
of PRADAXA
were
bleeding
and gastrointestinal
events (i.e., dyspepsia,
therapy.
Table
3
shows
the
number
of
patients
experiencing
bleeding
surgery/urgent
procedures;
In
life-threatening
or
uncontrolled
bleeding.
surgery/urgent procedures; In life-threatening or uncontrolled bleeding. nausea, upper abdominal
pain, gastrointestinal hemorrhage, and events in the poolednausea,
abdominal
pain, gastrointestinal
analysis upper
of RE-COVER
and RE-COVER
II studies hemorrhage, and
Hemodialysis
dabigatran;
the clinical experience diarrhea).
HemodialysisThe
can remove
dabigatran;at
however
the clinical
experience diarrhea). Bleeding [see
Ritz-Carlton
Reynolds
Plantation
Warningscan
andremove
Precautions]:
Tablehowever
2 shows
Bleeding
[see
Warnings
and
Precautions]:
Table 2 shows
during
theisfull
treatment including parenteral and oral only treatment
supporting
use of hemodialysis
a treatment
bleeding
limited
supporting the use of hemodialysis as a treatment for bleeding is limited the number of adjudicated
majorthe
bleeding
events duringasthe
treatmentforperiods
the number of adjudicated major bleeding events during the treatment
after randomization.
Greensboro,
[see with
Overdosage].
Prothrombin
complex
concentrates,
or
recombinant
[see Overdosage].
ProthrombinGA
complex concentrates, or recombinant period in the RE-LY study,
the bleeding rate per 100 subject-years
period in the RE-LY study, with the bleeding rate per 100 subject-years
be considered
butbytheir
has not
been
Factor VIIa may be considered but their use has not been evaluated (%). Major bleeding isFactor
Table
3 evaluated
Bleeding Events
in RE-COVER
and as bleeding accompanied by one or more
definedVIIa
as may
bleeding
accompanied
one use
or more
(%). Major
bleeding is defined
in clinicalin trials.
Protamine
sulfate
vitamin K are not expected
to ofIIthe
in clinical trials. Protamine sulfate and vitamin K are not expected to of the following: a decrease
RE-COVER
Treated
Patients
hemoglobin
of ≥2
g/dL,and
a transfusion
following:
a decrease in hemoglobin of ≥2 g/dL, a transfusion
affect
the
anticoagulant
activity
of
dabigatran.
Consider
administration
affect the anticoagulant activity of dabigatran. Consider administration of ≥2 units of packed
Period
red blood cells, bleeding at a critical site or
of ≥2Bleeding
units ofEvents-Full
packed redTreatment
blood cells,
bleeding at a critical site or
platelet concentrates
in included
cases where
thrombocytopenia is present with a fatal
of platelet concentrates in cases where thrombocytopenia is present with a fatal outcome.of Intracranial
Including
Parenteral
Treatment
hemorrhage
intracerebral
outcome.
Intracranial
hemorrhage included intracerebral
long-acting and
antiplatelet
drugs
have been used. Spinal/Epidural (hemorrhagic stroke), subarachnoid, and subdural bleeds.
or long-acting antiplatelet drugs have been used. Spinal/Epidural (hemorrhagic stroke), or
subarachnoid,
subdural
bleeds.
19neuraxial anesthesia (spinal/epidural
Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural
AnesthesiaNovember
or Puncture: When
PRADAXA
Warfarin
Hazard Ratio
anesthesia)
or spinal
puncture
is employed, patients treated with Table
anesthesia) or spinal puncture is employed, patients treated with Table 2 Adjudicated
c
Major Bleeding
Events
in Treated
2 twice
Adjudicated
Major Bleeding
Events
in Treated
150 mg
N (%)
(95% CI)
a
a
anticoagulant agents are at risk of developing an epidural or spinal
Patients anticoagulant age nts are at risk of developing an epidural or spinal
daily NPatients
(%)
hematoma which can result in long-term or permanent paralysis [see
hematoma which can result in long-term or permanent paralysis [see
PRADAXA
Event
PRADAXA
PRADAXA
PRADAXA
Boxed
Warning]. ToWarfarin
reduce the potential
risk of bleeding
Boxed Warning]. To reduce the potential risk of bleeding associated Event
Patientsassociated
N=2553
N=2554
Warfarin
150 mg
150 mg
150 mg
150 mg
withNthe
concurrentNuse
of dabigatran
and epidural orMajor
spinalbleeding
anesthesia/
with the concurrent use of dabigatran and epidural or spinal anesthesia/
a
=
5998
N
=
5998
37
(1.4)
51
(2.0)
0.73
event
=
6059
N
=
6059
vs.
Warfarin
vs.
Warfarin
b
analgesia
or b)spinal
puncture,
analgesia orHeart
spinal House
puncture, consider the pharmacokinetic profile
n (%/year
(%/yearb) HR (95% CI)
) consider
n (%/year
n (%/year(b0.48,
) n 1.11)
HR (95%the
CI) pharmacokinetic profile
of
dabigatran.
Placement
or
removal
of
an
epidural
catheter
or
of dabigatran.
Placement
or
removal
of
an
epidural
catheter
or
Washington, DC
Fatal bleeding
1 (0.04)
2 (0.1)
lumbar puncture is best performed when the anticoagulant effect of
lumbar puncture is best performed when the anticoagulant effect of
c
Major Bleedingc
Major7Bleeding
350 (3.47)
374 (3.58)
0.97
350 (3.47)
374 (3.58)
0.97
Bleeding
in a critical
(0.3)
15 (0.6)
dabigatran is low; however, the exact
timing
a sufficiently
low
dabigatran is low; however, the exact timing to reach a sufficiently low
(0.84,
1.12)to reacharea
(0.84, 1.12)
or
organ
anticoagulant effect in each patient is not known. Should the physician
anticoagulant effect in each patient is not known. Should the physician
hemoglobin
32 (1.3) Hemor-38 (1.5)
23 (0.22)
82 (0.77)
23 (0.22)
82 (0.77)
0.29
to administer
anticoagulation0.29
in the contextFallofin epidural
or Intracranial
decide to administer anticoagulation in the context of epidural or Intracranial Hemor- decide
d
≥2g/dL or
transfu- rhage (ICH)d
(0.18, 0.46)
(0.18, 0.46)
spinal anesthesia/analgesia or lumbar
puncture, monitor
frequently
spinal anesthesia/analgesia or lumbar puncture, monitor frequently rhage (ICH)
sion ≥2 units of
to detect any signs or symptoms of neurological impairment,
such
to detect any signs or symptoms of neurological impairment, such as
whole blood
or as
midline back pain, sensory and motor deficits (numbness,
midline back pain, sensory and motor deficits (numbness, tingling, or
packedtingling,
red bloodor
weakness in lower limbs), bowel and/or bladder dysfunction.
Instruct
weakness in lower limbs), bowel and/or bladder dysfunction. Instruct
cells
capsules, for oral use
BRIEF SUMMARY OF PRESCRIBING INFORMATION
Ohio Chapter Annual
Meeting 2016
Heart Valve Summit:
Medical, Surgical &
Interventional DecisionMaking Course
Michigan Chapter Annual
Meeting 2016
Missouri Chapter Annual
Meeting 2016
ACC Middle East
Conference 2016
Georgia Chapter
Annual Meeting 2016
Mid Atlantic Capital
Cardiology Symposium 2016
54 CardioSource WorldNews
Table 2 (Cont'd)
Event
PRADAXA
150 mg
N = 6059
n (%/yearb)
6 (0.06)
PRADAXA
150 mg
vs. Warfarin
HR (95% CI)
Hemorrhagic
40 (0.37)
0.16
Strokee
(0.07, 0.37)
Other ICH
17 (0.17)
46 (0.43)
0.38
(0.22, 0.67)
Gastrointestinal
162 (1.59)
111 (1.05)
1.51
(1.19, 1.92)
f
Fatal Bleeding
7 (0.07)
16 (0.15)
0.45
(0.19, 1.10)
ICH
3 (0.03)
9 (0.08)
0.35
(0.09, 1.28)
g
Non-intracranial
4 (0.04)
7 (0.07)
0.59
(0.17, 2.02)
a
Patients during treatment or within 2 days of stopping study treatment. Major
bleeding events within each subcategory were counted once per patient, but
patients may have contributed events to multiple subcategories.
b
Annual event rate per 100 pt-years = 100 * number of subjects with event/
subject-years. Subject-years is defined as cumulative number of days from
first drug intake to event date, date of last drug intake + 2, death date
(whatever occurred first) across all treated subjects divided by 365.25. In
case of recurrent events of the same category, the first event was considered.
c
Defined as bleeding accompanied by one or more of the following: a
decrease in hemoglobin of ≥2 g/dL, a transfusion of 2 or more units of
packed red blood cells, bleeding at a critical site or with fatal outcome.
d
Intracranial bleed included intracerebral (hemorrhagic stroke), subarachnoid,
and subdural bleeds.
e
On-treatment analysis based on the safety population, compared to ITT
analysis presented in Section 14 Clinical Studies.
f
Fatal bleed: Adjudicated major bleed as defined above with investigator
reported fatal outcome and adjudicated death with primary cause from
bleeding.
g
Non-intracranial fatal bleed: Adjudicated major bleed as defined above and
adjudicated death with primary cause from bleeding but without symptomatic
intracranial bleed based on investigator’s clinical assessment.
There was a higher rate of any gastrointestinal bleeds in patients
receiving PRADAXA 150 mg than in patients receiving warfarin (6.6%
vs. 4.2%, respectively). The risk of major bleeds was similar with
PRADAXA 150 mg and warfarin across major subgroups defined by
baseline characteristics (see Figure 1, below), with the exception of
age, where there was a trend towards a higher incidence of major
bleeding on PRADAXA (hazard ratio 1.2, 95% CI: 1.0 to 1.5) for
patients ≥75 years of age. Gastrointestinal Adverse Reactions:
Patients on PRADAXA 150 mg had an increased incidence of
gastrointestinal adverse reactions (35% vs. 24% on warfarin). These
were commonly dyspepsia (including abdominal pain upper, abdominal
pain, abdominal discomfort, and epigastric discomfort) and gastritislike symptoms (including GERD, esophagitis, erosive gastritis, gastric
hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and
gastrointestinal ulcer). Hypersensitivity Reactions: In the RE-LY study,
drug hypersensitivity (including urticaria, rash, and pruritus), allergic
edema, anaphylactic reaction, and anaphylactic shock were reported in
<0.1% of patients receiving PRADAXA. Treatment and Reduction in
the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary
Embolism: PRADAXA was studi ed in 4387 patients in 4 pivotal,
parallel, randomized, double-blind trials. Three of these trials were
active-controlled (warfarin) (RE-COVER, RE-COVER II, and RE-MEDY),
and one study (RE-SONATE) was placebo-controlled. The demographic
characteristics were similar among the 4 pivotal studies and between
the treatment groups within these studies. Approximately 60% of
the treated patients were male, with a mean age of 55.1 years. The
majority of the patients were white (87.7%), 10.3% were Asian, and
1.9% were black with a mean CrCl of 105.6 mL/min. Bleeding events
for the 4 pivotal studies were classified as major bleeding events if at
least one of the following criteria applied: fatal bleeding, symptomatic
bleeding in a critical area or organ (intraocular, intracranial, intraspinal
or intramuscular with compartment syndrome, retroperitoneal bleeding,
intra-articular bleeding, or pericardial bleeding), bleeding causing a fall
in hemoglobin level of 2.0 g/dL (1.24 mmol/L or more, or leading to
transfusion of 2 or more units of whole blood or red cells). RE-COVER
and RE-COVER II studies compared PRADAXA 150 mg twice daily and
warfarin for the treatment of deep vein thrombosis and pulmonary
embolism. Patients received 5-10 days of an approved parenteral
anticoagulant therapy followed by 6 months, with mean exposure of 164
days, of oral only treatment; warfarin was overlapped with parenteral
therapy. Table 3 shows the number of patients experiencing bleeding
events in the pooled analysis of RE-COVER and RE-COVER II studies
during the full treatment including parenteral and oral only treatment
periods after randomization.
Warfarin
N = 5998
n (%/yearb)
Table 3 Bleeding Events in RE-COVER and
RE-COVER II Treated Patients
Bleeding Events-Full Treatment Period
Including Parenteral Treatment
PRADAXA
Warfarin
150 mg twice
N (%)
daily N (%)
Patients
Major bleeding eventa
N=2553
37 (1.4)
N=2554
51 (2.0)
Fatal bleeding
Bleeding in a critical
area or organ
Fall in hemoglobin
≥2g/dL or transfusion ≥2 units of
whole blood or
packed red blood
cells
1 (0.04)
7 (0.3)
2 (0.1)
15 (0.6)
32 (1.3)
38 (1.5)
Hazard Ratio
(95% CI)c
0.73
( 0.48, 1.11)