Intent of Session
Our goal:
 To educate and empower pharmacists on the chronic
management of atrial fibrillation so that they may competently
and confidentlyy improve
p
the care of the patients
p
theyy serve.
Update on the Chronic Management
of Atrial Fibrillation
 Engage you in discussion and with activities…
AzPA Annual Meeting
July 2011
 Have fun!
Lindsay Davis, Pharm.D.
Assistant Professor – Midwestern University College of Pharmacy
“ Tell me and II’llll forget;
Show me and I may remember;
Involve me and I’ll understand. ”
Andrew Varker, Pharm.D.
Clinical Pharmacist – Phoenix VA Medical Center
1
- Chinese Proverb
2
Learningg Objectives
j
After attending this CPE session and actively participating in the
activities,
ti iti participants
ti i t should
h ld bbe able
bl tto:
3
1)
Develop a treatment plan for appropriate antithrombotic therapy for
unique patients with atrial fibrillation based on patient-specific risk
factors
2)
Compare and contrast medications used in the chronic management of
atrial fibrillation
3)
Select an appropriate anti-arrhythmic agent for the maintenance of
normal sinus rhythm for a given patient case scenario when
considering co-morbid conditions and renal function
4
Meet our p
patient: Art B. Toofast
5
CC:
“I was just discharged from the hospital and was told I had a funny
hheartt rhythm
h th andd now I’
I’m on allll these
th new meds
d”
HPI:
Mr. Toofast is a 77 y/o male who presents today to the cardiology clinic
pharmacist for follow-up
follow up and education after having been hospitalized for
new onset Afib with RVR
PMH:
New onset Afib
Hyperlipidemia
CAD s/p DES 4 months ago
COPD – O2 dependent
Osteoporosis s/p fracture of left shoulder after a fall 4 years ago
Unprovoked
U
k d DVT 8 years ago  treatedd with
i h warfarin
f i x 3 months
h
h/o Hep C while in the service
Meet our p
patient: Art B. Toofast
Meds:
to be continued for total of one year
Warfarin 4 mg PO once daily – new med
Diltiazem XR 240 mg PO once daily – new med
Simvastatin 40 mg PO once daily
Ti
Tiotropium
i - inhale
i h l contents off one capsule
l once ddaily
il
Advair 250/50 one puff PO twice daily
p
Albuterol MDI prn
Calcium 500 mg PO twice daily with food
Vitamin D 400 IU PO twice daily
6
Treatment of Atrial fibrillation
Meet our p
patient: Art B. Toofast
I. Stroke Prevention
 Appropriate Antithrombotic therapy based on individual patient risk
f
factors
for
f stroke
k
 Antiplatelet therapy with aspirin +/- clopidogrel
 Anticoagulation therapy with warfarin or dabigatran
Today’s Vital Signs:
BP
138/82 mm Hg
HR
100 bpm (regular)
RR
20 breaths/minute
Temp 37o C
INR values:
l
Date
11 days
y ago
g
6 days ago at hospital discharge
3 days ago
today
7
ASA 81 mg PO once daily
Clopidogrel 75 mg PO once daily - started 4 months ago post stenting,
II. Treatment of Tachyarrhythmia
 Rate-control
INR
1.1
2.1
2.6
2.4
 Chronotropic drugs
 Ablation of AV node and implantation of a pacemaker
Dose
warfarin initiated
4 mg daily
4 mg daily
4 mg daily
 Rhythm-control
 Cardioversion: electrical or pharmacological (spontaneous cardioversion can occur
at random)
 Maintenance of normal sinus rhythm with antiarrhythmic drugs
 Pulmonary vein isolation via ablation
 Implantable atrial defibrillators
8
Antithrombotic Therapy
Risk Factors for Stroke in AF
Antithrombotic
Therapy
 Ischemic stroke is the most devastating complication of AF
 Cerebral thromboembolism from a cardioembolic source
Alters one or more
steps in the
coagulation cascade
 15 – 20% of all ischemic strokes occur in patients with AF
 Annual risk of ischemic stroke in patients with AF who
Anticoagulant
Therapy
DO NOT receive antithrombotic therapy
py ranges
g from
2 – 18 % depending on individual risk factors
Antiplatelet
Therapy
Slows the rate of
coagulation
 More than 80% of thromboembolic events occur during the
first 3 days after cardioversion (pharmacologic, electrical or
spontaneous)
Inhibits actions of
platelet binding
10
Risk Factors for Stroke in AF
Antithrombotic therapy
 CHADS2 Scoring System is a validated classification scheme that
 CHEST 2008 GUIDELINES
helps to quantify the stroke risk in Afib patients
CHF
HTN
Age > 75
DM
Stroke/TIA
1 point
i t
1 point
1 point
1 point
2 points
6 points max
 Annualized stroke risk based on CHADS2 Score
0 points:
1 point:
2 points:
points
3 points:
4 points:
5 points:
6 points:
11
1.9 %/yr
2.8 %/yr
4 0 %/yr
4.0
%/ r
5.9 %/yr
8.5 %/yr
12 5 %/yr
12.5
18.2 %/yr
Gage BF, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial
Fibrillation. JAMA. 2001; 285:2864-70.
 RF for stratification: CHADS2 Score (CHF, HTN, Age > 75, DM, CVA/TIA)
 Goal
G l INR 2 – 3;
3 ttargett 22.55
High
g Risk
*
(4 to > 18%)
Regardless of
CHADS2 Score
prior ischemic stroke, TIA, systemic embolism Warfarin
Mitral valve stenosis Warfarin
Prosthetic heart valve Warfarin

(at intensity appropriate for valve)
CHADS2 Score > 2 Warfarin
Intermediate
Risk
(2 to 8%)*
Low Risk
(1.9%)*
CHADS2 Score = 1
Warfarin or ASA 75 – 325 mg daily
Warfarin >> ASA
If CHADS2 Score = 1 (Age > 75 ONLY)  ASA 75 – 325 mg daily
CHADS2 Score
S
= 0 ASA 75 – 325mg daily
*annualized stroke risk
12
Singer DE, et al. Antithrombotic therapy in atrial fibrillation. American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines (8th Ed). CHEST. 2008;133:546S–592S
Risk vs Benefit of Anticoagulation
g
Fall risk
 PMH (TIA/ CVA? Thromboembolism? GI bleed?)
 Increased risk of falls occurs with increasing age
 Elderly have a mean 1.81 falls per year
 10% of falls result in serious injury
 Monitoring non-compliance vs unavailability
 Medication non-compliance
 Patient choice
 Dementia
Environmental
 Alcoholism
Al h li
 Elderly (increased risk of falls)
60
50
58
61
57
44
35
40
30
20
10
0
< 55
55-64
65-74
75-84
> 85
Age (years)
Under-estimation of benefit
 Stroke relative risk reduction
 Aspirin = 21%
 Warfarin = 68%
Medications
Dementia / AMS
Arthritis
Vision disturbance
g / weakness
Decreased muscle strength
Epilepsy
Anatomical deformities
Hearing difficulty
I
Impaired
i d sensation
ti
Incontinence
Infection/fever
Parkinson's / Poor balance
Previous fractures / amputation
Vertigo
Analgesics
l
Anti- depressants
Anti-hypertensives / diuretics
Anti-histamines
Anti-psychotics
Benzodiazepines
Ethanol
H
Hypnotics
ti
Insulin/anti-diabetics
Muscle relaxants
p
Neuroleptics
Psychotropics
Vasodilators
Preventable events with underuse of warfarin
Over-estimation of risk
 Estimated rate of ICH/year
y
 Aspirin = 0.2%
 Warfarin = 0.3-0.6%
14%
12%
10%
8%
6%
4%
2%
0%
Ev
vent Raate
Warfarin U
W
Use in Elig
gible
Patieents (%)
Underutilization of warfarin
80
70
Intrinsic
Clutter
l
on flfloor
Ill-fitting shoes
Improper furniture height
Lack of assistive devices
Long travel distances
Long pant legs
Loose rugs
P lighting
Poor
li hti
Slippery surfaces
Stairs
Uneven floors
Unsafe transfers
Unstable furniture
(p < 0.05)
10.8%
(p < 0.05)
3.7%
7.8%
(p = NS)
4.4% 4.9%
4.5%
I h
Ischemic
Stroke
S k
Th
Thromboembolism
b
b l
Warfarin Therapy
H
Hemorrhage
h
Warfarin Candidate
Darkow T., et al. Curr Med Res Opin. 2005;21:1583-94
How many times do you really have to fall?
Patient Case: Art B. Toofast
 What is Mr. Toofast’s CHADS2 score?
 Man-Song-Hing et al. (1999)
 QALY highest for warfarin therapy for all patients with atrial
 What antithrombotic therapy is Mr. Toofast currently on?
fibrillation
 Warfarin had the highest QALY for all levels of risk
 Average fall risk:
 535 fold greater risk of SDH than non- fallers for warfarin to NOT be
 Is his current therapy appropriate?
consider preferred therapy (295


falls)
29 fold greater risk of ICH… (16 falls)
14 fold
f ld greater
t risk
i k off non-CNS
CNS bleed…
bl d (8 falls)
 Do you have any recommendations or concerns about his current
 Patients 65 and older have the greatest benefit from warfarin
therapy
py
18
Antithrombotic therapy
2011 ACCF Guideline Updates
p
 What might the stratification of antithrombotic therapies look like in
Recommendations for Emerging Antithrombotic Agents
and Combining Anticoagulant with Antiplatelet Therapy
Recommendation
relation to CHADS2 score with the new updates?
Class
Dabigatran is useful as an alternative to warfarin for the prevention of
stroke and systemic thromboembolism in patients with paroxysmal to
permanent AF and risk factors for stroke or systemic embolization who do not
have a prosthetic heart valve or hemodynamically significant valve disease,
severe renal failure (CrCl < 15 mL/min) or advanced liver disease (impaired
baseline clotting function)
J Am Coll Cardiol. 2011;57(11):e101-98.
I
The addition of clopidogrel to aspirin to reduce the risk of major vascular
events, including stroke, might be considered in patients with AF in whom
orall anticoagulation
i
l i with
i h warfarin
f i iis considered
id d unsuitable
i bl ddue to patient
i
preference or the physician’s assessment of the patient’s ability to safely sustain
Circulation. 2011;123(1):104-23.
anticoagulation
IIb
19
antithrombotic regimen?
 Mr.
M Toofast
T f states that
h hhe hhas hhadd no problem
bl remembering
b i to take
k
all of his medications, but he is still unclear why he needs a medicine
to “thin his blood” to pprevent a stroke when he has a “heart pproblem”
and not a “brain problem” … how do you respond?
L l off
Level
Evidence
High Risk
*
(4 to > 18%)
Regardless of
CHADS2 Score
B
CHADS2 Score > 2
B
Class I: Benefit >>> Risk “treatment
“
SHOULD be administered””
Class IIb: Benefit > Risk
“treatment MAY BE considered”
Level B: Limited populations evaluated; data derived from a single RCT or nonrandomized studies
Intermediate
Risk
(2 to 8%)*
Low Risk
(1.9%)*
h/o ischemic CVA/TIA, systemic embolism Warfarin or
Dabigatran or ASA + Clopidogrel (if contraindications to
anticoagulation tx)
Prosthetic heart valve or hemodynamically significant valve disease
Warfarin (at intensity appropriate for valve)
Warfarin or Dabigatran or ASA + Clopidogrel (if contraindications
to anticoagulation tx)
Warfarin or Dabigatran or ASA 75 – 325 mg daily
CHADS2 Score = 1
Dabigatran >Warfarin >> ASA
If CHADS2 Score = 1 (Age > 75 ONLY)  ASA 75 – 325 mg daily
CHADS2 Score = 0 ASA 75 – 325mg daily
*annualized stroke risk
20
Singer DE, et al. Antithrombotic therapy in atrial fibrillation. American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines (8th Ed). CHEST. 2008;133:546S–592S
Antithrombotic Therapy
py Comparisons
p
TREATMENT COMPARISONS
 This is a common antithrombotic regimen seen in practice, especially in
RRR (95% CI)
M
Meta-analyses
l
off the
h efficacy
ffi
off antithrombotic
ih
b i therapies
h
i for
f prevention
i off ischemic
i h i
stroke in AF from pooled data of randomized trials
Chest. 2008;133:546s-92s.
Adjusted-dose warfarin vs. No antithrombotic therapy
68% (50-79)
ASA vs. No antithrombotic therapy
21% (0-38)
Ad
Adjusted-dose
d d warfarin
f
vs. ASA
52% (37-63)
(37 63)
Randomized controlled trials for primary prevention of stroke or systemic embolism
J Am Coll Cardiol. 2011;57(11):e101-98.
( )
Circulation. 2011;123(1):104-23.
( )
21
Triple Therapy? Warfarin + ASA + Clopidogrel
Warfarin vs. ASA + Clopidogrel
42%
ASA + Clopidogrel vs. ASA
11%
Dabigatran 150mg BID vs. Adjusted-dose warfarin*
34%
* RE-LY was an ITT analysis; TTR 64% for warfarin group
patients with newly placed coronary stents
? Increased efficacy
? Decreased safety
2011 ACCF/AHA/HRS Focused Update:
p
 “The combined use of dual-antiplatelet therapy with both clopidogrel
and ASA plus warfarin has been suggested as a strategy for treatment and
prevention off complications
l
off 2 or more coexisting conditions
d
suchh as
AF, mechanical valve prosthesis, or the presence of a drug-eluting
coronaryy stent.”
 “This strategy is associated with an increase in bleeding complications
that might range from mild or moderate to severe or life threatening.”
 “No
“ prospective randomized trials have been reported addressing this
important clinical issue.”
22
RE-LY Trial (N Engl J Med; September 2009)
RE LY Trial (N Engl J Med; September 2009)
RE-LY
Goal: To compare the rate of stroke (ischemic or hemorrhagic) or systemic
embolism in AF ppatients treated with Warfarin vs. Dabigatran
g
 Multicenter, open-label, randomized controlled trial including > 18,000
patients who were > 64 years with AF and > 1 risk factor for ischemic
stroke (CHADS2, h/o systemic embolism, age 65-74 with DM or CAD)
 Treatment groups:
 Adjusted-dose Warfarin (Goal INR 2 – 3); TTR 64.4%; INR tested > monthly
 Dabigatran 110mg PO BID
 Dabigatran 150mg PO BID
 Median duration of follow-up was 2 years, mean CHADS2 = 2.1
 Excluded
E l d d patients
i
with
ihC
CrCl
Cl < 30 mL/min
L/ i
23
 Concomitant use of antiplatelets permitted (ASA dose < 100 mg/day)
24
RE-LY Trial (N Engl J Med; September 2009)
RE-LY Trial ((N Englg J Med; September
p
2009))
25
26
2011 ACCF Guideline Update
 “Because of the twice-daily dosing and greater risk of
nonhemorrhagic side effects with dabigatran, patients already
taking warfarin with excellent INR control may have little to
gain by switching to dabigatran.
dabigatran ”
 “Patients with AF and at least 1 additional risk factor for
stroke who could benefit from treatment with dabigatran as
opposed to warfarin should consider individual clinical
features including
features,
including…”
 the ability to comply with BID dosing
 availability of an anticoagulation monitoring program to monitor INR
 patient preference
f
27
 cost
J Am Coll Cardiol. 2011;57(11):e101-98.
28
Dabigatran
Dabigatran
PROs
 Dabigatran150mg
g
g PO BID was SUPERIOR to Warfarin for prevention
p
of
stroke (hemorrhagic or ischemic) & systemic embolism in RE-LY trial
 NNT for one year is ~169 for dabigatran, ~175 for warfarin
 “No monitoring required”
 Who will follow-up with patient regularly to monitor for signs
/symptoms
/sy
pto s oof bleeding?
ee g?
 Patient contact time for education and encouragement to be compliant
 “accountability”
CONs
 Increased pure drug cost & difficult storage requirements (moisture sensitive capsules)
 Less clinical experience  75 mg BID dose for CrCl 15 – 30 mL/min not studied in RE-LY trial
 BID dosing  ? decreased compliance
 ?? Increased rate of MI
 Dyspepsia & GI bleeding  ok to use in patients with GERD, GI ulcers, or recent h/o GI bleed ?
 ECT & TT are not commonly available tests as of yet  how can we ensure patients are therapeutic?
 INR can NOT be used to monitor Dabigatran’s
g
effectiveness due to insensitivityy ((INR +/- elevated))
 No reversal agent … supportive measures can be used: FFP, PRBC, surgical intervention if appropriate
Consider that the t ½ of dabigatran is “short” (12-17 h) & reversal of warfarin with vitamin K takes ~ 24 h
Dabigatran
g
is dialyzable
y
(in cases of OD)


 Renally excreted dose adjustments required
 Bridging not necessary based on quick onset of action
 Decreased
D
d risk
i k off major
j bl
bleeding
di vs. W
Warfarin
f i
29
Dabigatran reliably prolongs aPTT, ECT, TT
Patient Case: Art B. Toofast
How should patients be managed if renal function becomes unstable?

 Prodrugg of dabigatran
g
is a substrate for P-glycoprotein
gy p
 changes
g in efficacy/safety
y
y?
30
Self-Assessment Q
Question #1
 Do the new guideline updates change your recommendation for
Which of the following statements is TRUE regarding
antithrombotic therapy in patients with atrial fibrillation?
Mr. Toofast’s
’ antithrombotic regimen?
a) Clopidogrel plus aspirin is an appropriate regimen in patients whom
oral anticoagulation with warfarin is considered unsuitable.
 Discussion…
D
b) Target INR for warfarin therapy is 2.5 – 3.5 for most patients with
atrial fibrillation.
fibrillation
c) Dabigatran has been demonstrated to be inferior to warfarin therapy
in clinical trials.
d) Aspirin therapy should NOT be considered as the sole antithrombotic
agent in patients with atrial fibrillation.
31
32
Treatment of Atrial fibrillation
Rate-Control Strategy
I. Stroke Prevention
 Appropriate Antithrombotic therapy based on individual patient risk
f
factors
for
f stroke
k
 Antiplatelet therapy with aspirin +/- clopidogrel
 Anticoagulation therapy with warfarin or dabigatran
• Rate control = Symptom control (minimize swings in HR)
II. Treatment of Tachyarrhythmia
 Rate-control
• Consider rate-control as first line therapy (unless contraindicated)
• Palpitations, chest pain, shortness of breath, syncope
• P
Prevent excessive
i tachycardia
h
di
• Excessive tachycardia can lead to tachycardia-associated cardiomyopathy
• Goal HR ??
 Chronotropic drugs
 Ablation of AV node and implantation of a pacemaker
 Rhythm-control
 Cardioversion: electrical or pharmacological (spontaneous cardioversion can occur
at random)
 Maintenance of normal sinus rhythm with antiarrhythmic drugs
 Pulmonary vein isolation via ablation
 Implantable atrial defibrillators
Age > 65
•
CAD
•
Contraindication to antiarrhythmic drugs
•
Unsuitable for cardioversion
•
Decompensated systolic heart failure (HF)
• Medications
•
33
Beta-blockers, Non-dihydropyridine Calcium Channel Blockers, Digoxin
34
Timeline: the rise of rate-control
2011 ACCF Guideline Updates
p
HOT-CAFE : Rate = Rhythm?
STAF : Rate = Rhythm
2010
2009
2007
2008
2006
2005
2004
2003
2002
2001
2000
Rhythm
control
STRICT rate-control
Recommendation for Rate Control During Atrial Fibrillation
RACE II:
Lenient rate =
St i t rate
Strict
t
Post-hoc (RACE vs AFFIRM) :
Lenient rate = Strict rate
LENIENT
rate-control
Recommendation
Class
Level of
Evidence
Treatment to achieve strict rate control of heart rate (< 80 bpm at
rest or < 110 bpm during a 6-minute walk) is not beneficial
compared to achieving a resting hear rate < 110 bpm in patients
with persistent AF who have stable ventricular function (left
ventricular ejection fraction > 0.4) and no or acceptable symptoms
related to the arrhythmia, though uncontrolled tachycardia may
over time
i b
be associated
i d with
i h a reversible
ibl decline
d li in
i ventricular
i l
performance.
N Engl J Med. 2010;362:1363-73
III
B
Class III: No benefit
“not helpful”
L l B:
Level
B Limited
Li i d populations
l i evaluated;
l
d data
d dderived
i d from
f
a single
i l RCT or nonrandomized
d i d studies
di
AFFIRM : Rate > Rhythm
 Canadian Cardiovascular Society Atrial Fibrillation Guidelines 2010:
RACE : Rate = Rhythm
35
•
PIAF : Rate = Rhythm
Rate and Rhythm Management
36
 Resting heart rate goal of < 100 bpm
Determination of effect on BP
Beta Blockers
 Competitively block beta-adrenergic stimulation
BP = CO x SVR
CO = HR x SV
 Decreased HR
 Decreased myocardial contractility
 Decreased BP
BP = HR x SV x SVR
HR
SV
Beta blocker
bl k
CCB(non-DHP)
Clonidine
Beta bl
blocker
k
CCB (non-DHP)
Clonidine
37
 Decreased
ec ease oxygen
o yge demand
e a
 Titrate dose to goal HR
SVR
ACEi
C / ARB
CCB (DHP) + verapamil
Clonidine
Hydralazine /Monoxidil
Beta blocker (non-selective)
Diuretics
Alpha blocker
Miscellaneous
Calcium Channel Blockers (non-DHPs)
38
 Binds competitively to Na-K-ATPase slowing the development
of Na gradient and subsequent AV node conduction
transduction at SA and AV nodes
 Decreased HR
 Decreased HR
 Increased myocardial contractility
 Decreased myocardial
y
contractilityy
 No change
g in BP
BP = ( HR x SV) x SVR
BP = ( HR x SV)) x SVR
 Used to control ventricular response rate in AF
 Slows heart rate AT REST (not during exercise)
 Decreased oxygen demand
 Titrate dose to goal HR
 NOT recommended for monotherapy
 Available drugs:
 Synergistic with beta-blockers / Ca2+ channel blockers
 Diltiazem
 Drug-drug interaction with verapamil – (may require decreased digoxin dose)
 Verapamil
39
Adrenergic Receptor Blocking Activity
1 SELECTIVE
S
CT
NON-SELECTIVE
O S
CT
( & )
acebutolol
carteolol
carvedilol (also active on alpha-1)
atenolol*
betaxolol
labetalol* (also active on alpha-1)
bisoprolol
nadolol
**
*
esmolol
ppropranolol
p
*
metoprolol tartrate
metoprolol succinate
* available IV ** available IV ONLY
Digoxin
 Inhibit AV node conduction by depressing signal
 Decreased BP
BP = ( HR x SV) x SVR
 Renal dose adjustment required!
40
 Improves systemic circulation
 Results in increased renal perfusion, & reduced edema
Compelling indications for specific drugs
Patient Case: Art B. Toofast
 Beta blockers
 Mr. Toofast has a resting heart rate of 100 bpm.
 HF (systolic / diastolic)
 What is his goal heart rate
 CAD
 What medication(s) is he on for rate-control? Is this appropriate
 Calcium channel blockers (non-DHP)
(
)
therapy for him?
 Chronic renal dysfunction
 Conditions limiting the use of beta blockers (i.e., COPD / asthma)
 Mr Toofast
Toofast’ss resting heart rate increases to 120 bpm. How would
 Digoxin
you augment his current rate control therapy?
 HF (systolic / diastolic)
 Hypotension
 Sedentary / bed-bound
41
42
Self-Assessment Q
Question #2
Which of the following DOES NOT represent a reasonable
rate control option that can be used in a patient with chronic
atrial fibrillation?
Rhythm-Control Strategy
 Goal is to restore and maintain normal sinus rhythm
 Cardioversion is used to restore NSR
Direct current cardioversion (DCCV)
a) Metoprolol
b) Diltiazem
c) Digoxin
d) Amlodipine
(~15% of patients remain in NSR at 1 year)
43
44
Pharmacological (PCV)
Rhythm-Control Strategy
Rhythm-Control Strategy
 Before initiating antiarrhythmic drug therapy, treatment of precipitating
or reversible causes of AF is recommended (ACCF class I recommendation)
 Specific antiarrhythmic drug choice depends on:
Presence of underlying structural heart disease
 Precipitating events: alcohol “Holiday Heart”, cardio-thoracic surgery
(poor LV function, LV hypertrophy, CAD, valvular disease)
 Reversible causes: HYPERthyroidism
Renal function
Potential toxicities (adverse drug events,
events drug
drug-drug
drug interactions)
 Consider rhythm-control (DCCV or PCV) for patients:
 Who are hemodynamically unstable and rate-control agents are contraindicated
 Who are younger, < 60 years
 When rate control agents are not effective (unable to achieve resting HR < 80 bpm)
 Who have disabling symptomatic AF despite max rate control (resting HR < 80 bpm)
 Who are presenting for the 1st time with “Lone AF”
 Who are physically active & have poor exercise tolerance with rate control agents
45
Provider comfort and experience (i.e., is the provider registered as a Tikosyn®
prescriber, is the hospital and retail pharmacy approved for dispensing Tikosyn®)
Logistics
L
(inpatient
(
vs. outpatient initiation))
 N
Needd careful
f l monitoring
i i to minimize
i i i adverse
d
ddrug events & toxicities
i ii
Proarrhythmias, extra cardiac toxicities, hospitalizations
46
AFFIRM Trial (N Engl J Med; December 2002)
Goal:
AFFIRM Results
To compare all-cause mortality for AF patients
treated with Rate vs. Rhythm
y
Control
 Multicenter Randomized Controlled Trial including > 4,000 patients
who were > 65 yyears with AF and > 1 risk factor for ischemic stroke
47
 Treatment groups:
 Rhythm
y
Control Group:
p
 Cardioversion  treatment with antiarrhythmic drugs to maintain NSR
o Continuous anticoagulation encouraged (INR 2 – 3) but could be stopped at
physician’ss discretion if sinus rhythm maintained > 4 weeks
physician
 Rate Control Group:
 Rate-controlling drugs, allowing AF to persist
o Goal
G l HR < 80 att rest;
t < 110 during
d i 66-minute
i t walk
lk test
t t
o Protocol mandated continuous anticoagulation (INR 2 – 3)
48
Conclusions & Impact of AFFIRM Trial
Outcome
Rate-Control
Group
n = 2027
Rhythm-Control
Group
n = 2033
P-value
TdP
0.2%
0.8%
0.007
Prolongation of
QTc interval
(>520 msec)
0.3%
1.9%
<0.001
Hospitalizations
(after baseline)
73%
80.1%
<0.001
Pulmonary
events
1.7%
7.3%
<0.001
Gastrointestinal
events
2.1%
8.0%
<0.001
Bradycardia
4.2%
6.0%
0.001
Conclusions & Impact of AFFIRM Trial
 No difference in all-cause mortality
Conclusion
 Rates of ischemic stroke ~1%
1% per year in both groups
 Trend toward increased mortality associated with rhythm-control
Rate-Control group had
a lower incidence of :
 Trend towards difference in mortality did not begin to emerge until near the 2nd
year of follow-up
follow up
TdP
Prolonged QTc interval
Hospitalizations
Pulmonary events
GI events
B d di
Bradycardia
 This studyy resulted in an about-face in the presumed benefits of
rhythm-control therapy
 ACC/AHA/ESC 2006 Guidelines changed priority of
AF treatment to rate-control plus antithrombotic therapy
as first-line therapy for most patients
49
50
Recommendations for Maintenance of NSR in AF
2011 ACCF Guideline Updates
Drug
Amiodarone
Route
Oral
Dose for Maintenance
100 – 400 mg daily 200 mg daily (most common)
Lowest effective dose preferable
Angina, h/o MI / CABG /
coronary stenting,
known coronary
atherosclerosis
th
l
i
Wall thickness > 1.4 cm
Measured via ECHO
80 – 160 mg bid
LVEF
< 35-40%
Sotalol
Oral
500 mcg bid
Orall
MUST ADJUST DOSE if CrCl < 60 ml/min
CONTRAINDICATED if CrCl < 20 ml/min
Contraindications to Select Antiarrhythmic Agents
* Appropriate
antithrombotic therapy
should continue to be
provided indefinitely
based on individual risk
factors for stroke
51
Circulation. 2011;123(1):104-23.
Drug
est CrCl
(mL/min)
Baseline QT/QTc interval
(msec)
Amiodarone
n/a
n/a
Dronedarone
n/a
QTc > 500
Dofetilide
< 20
QTc > 440
Sotalol
< 40*
QT > 450
TdP (contraindicated if baseline QT > 450 msec) hypotension, bradycardia, AV Block, fatigue, dizziness, MUST ADJUST DOSE if CrCl < 60 ml/min dyspnea, bronchospam, HF exacerbation decrease to once daily dosing
CONTRAINDICATED if CrCl < 40 ml/min
Dofetilide
f ilid
Monitoring/Clinical Pearls
Hypotension, bradycardia, AV Block, QT prolongation, TdP (rare), pulmonary toxicity, neurologic disturbances, thyroid toxicity, optic neuropathy, corneal microdeposits, GI upset, constipation, skin discoloration, photosensitivity, liver toxicity, drug‐drug interactions (e.g. warfarin, simvastatin, digoxin)
Dronedarone
Oral
400 mg bid
Flecainide
Oral
50 – 150 mg bid
Propafenone
Oral
150 – 300 mg q8h
(contraindicated in systolic HF)
TdP (contraindicated if baseline QTc > 440 msec) Keep K+ > 4, Mg2+ > 2, headache, dizziness, contraindicated with certain medications (e.g. HCTZ, verapamil, cimetidine, ketoconazole, any drug that prolongs QTc interval)
GI upset (N/V/D), take w/meals to increase absorption, ? pulmonary toxicity, Contraindicated in NYHA Class IV HF or Class II or III with recent decompensation, Contraindicated if baseline QTc > 500 msec, DDI (e.g. digoxin, clarithro, phenytoin, carbamazepine, St.John’s Wort, ? warfarin)
Hypotension, HA, blurred vision, Atrial flutter with high ventricular rate, Pt MUST be on AV‐nodal blocker (βB/CCB) prior to use
52
Amiodarone
 Mechanisms of Action: ((Effects all 4 Vaughn-Williams
g
Classes))
 Prolongs QT interval (K+ channel blockade)
 Slows heart rate & AV nodal conduction (β-receptor & Ca2+ channel blockade)
 Prolongs refractoriness (K+ & Na+ channel blockade)
 Slows intracardiac conduction (Na+ channel blockade)
 t ½ ~ 60 days
(requires prolonged loading period, ADE (including DDI) can occur for months after drug d/c, will accumulate in tissues)
 Therapeutic Uses (non-FDA approved indications):
 p
pretreatment for DCCV to enhance success & pprevent recurrence
 used as PCV agent to convert patients with AF into normal sinus rhythm
 used to maintain normal sinus rhythm in patients who have been cardioverted
 used to control heart rate in AF patients with heart failure (βB & CCB properties)
 Contraindications:
 Severe sinus-node dysfunction
 2nd/3rd degree heart block or bradycardia causing syncope (unless pt has artificial pacemaker)
53
 Cardiogenic shock
 Pregnancy
Amiodarone:
Surveillance Strategy
Siddoway LA. Amiodarone: Guidelines for use and monitoring.
Am Fam Physician. 2003; 68:2189-96.
Amiodarone: Potential Toxicities
-most serious potential ADE:
PULMONARY FIBROSIS
- can be life-threatening
- occurs in 2 – 17% of pts
- may occur without sx
(most common clinical
presentation is cough,
progressive dyspnea,
patchy infiltrates of CXR,
& reduced PFTs)
- occurs most freq. with
doses > 400 mg/day
- can be reversible if caught
earl ttx stopped
early,
stopped, &
systemic corticosteroid
neurologic:
tmt started
tremor, ataxia,
- NEVER retry patient
peripheral
on amiodarone
neuropathy
th
54
thyroid toxicity (10% of patients)
HYPO- (more common) or HYPERbradycardia / proarrythmia (uncommon)
liver toxicity: elevated LFTs
(occurs at a rate of 0.6 % annually)
nausea / constipation:
p
((30% of p
patients))
photosensitivity / blue discoloration of skin
(occurs in < 9% of patients), drug highly lipophilic
pregnancy: may cause fetal harm (thyroid)
Many drug-drug interactions: warfarin, statins
(esp simvastatin), digoxin, phenytoin,
verapamil, diltiazem, ciprofloxacin,
azithromycin, grapefruit juice, many others.
The effects may take WEEKS to peak!
The frequency of most adverse events related to total amiodarone exposure (i.e., dosage & duration of tx).
Use the lowest effective dosage & discontinue treatment (when possible) if adverse events occur.
Dronedarone
 Class
Cl III AAD that
h exhibits
hibi properties
i off allll 4 Vaughn-Williams
V h Willi
classes
l
(same electrophysiologic profile as amiodarone)
Patients being treated with amiodarone
should be followed regularly to assess:
- Continued need for therapy
- Efficacy of therapy
- Appropriateness of dosage
- Adverse drug events
- Potential drug interactions
 Non-iodinated derivative of amiodarone  shorter t½, less lipophilic
 Not currently associated with amiodarone-like adverse effects such as thyroid toxicity
& pulmonary toxicity per available clinical trials and safety data
(mean follow-up only 21 months… in many cases, patients treated with amiodarone develop
pulmonary toxicity > 2 years after initiation)
 Indication: To reduce the risk of CV hospitalization in patients with paroxysmal or
It is advisable to have a comprehensive
plan with documentation that is
consistent across all patients/providers.
persistent AF or Aflutter who have cardiovascular risk factors (HTN, advanced age, DM,
CVA, LVEF < 40%)
 Drug-Drug Interactions:
Pharmacists have an important &
valuable role in amiodarone monitoring.
We see the patient each time the
prescription is filled !
 digoxin (empirically decrease dose by 50%)
 contraindicated with strong CYP3A4 inhibitors/inducers (e.g.
(e g clarithromycin
clarithromycin, voriconazole
voriconazole,
cyclosporine, phenytoin, carbamazepine, St. John’s Wort)
 ? Warfarin (controversial)
Have your patients been comprehensively
educated on amiodarone?
55
optic neuropathy/neuritis (rare)
corneal microdeposits (very common)
pulmonary toxicity:
 Can cause dose-dependent
dose dependent prolongation of QTc interval (TdP rare)
56
 Modest efficacy: Amiodarone >> Dronedarone
Dronedarone
Dronedarone
 Contraindications:
 NYHA Class IV HF OR NYHA Class II/III HF with recent decompensation
 2ndd or 3rdd degree
d
AV Block,
Bl k sickk sinus syndrome,
d
b d d (<
bradycardia
( 50 bbpm))
 Baseline QTc interval > 500 msec or PR interval > 280 msec
 Severe hepatic impairment
 Pregnancy (category X) or lactation
 REMS (Risk Evaluation & Mitigation Strategy) Program [FDA]
 mPACT
PACT (Multaq
(M lt ® Partnership
P t
hi for
f Appropriate
A
it C
Care andd T
Treatment
t
t
 Goal: Prevent dronedarone exposure to patients with:
 NYHA Class IV HF OR
 NYHA Class II or III with recent decompensation requiring hospitalization or referral to
specialized heart failure clinic
 MUST monitor patients for HF decompensation during treatment!
 Elements of program:
 Increases SCr by inhibition of tubular secretion
 SCr may increase by ~ 0.1 mg/dL within one week of treatment intitiation
 No evidence of effect on true GFR
 No dosage adjustment required for renal dysfunction
 Side effects:
 Most common: diarrhea, which may necessitate drug discontinuation
 Others: nausea, abdominal pain, vomiting, asthenia
57
Dronedarone –
Summary of Clinical Trials
 FDA-required Medication Guide to be given with each new and refill
prescription
 Health care professional information sheet
 REMS print advertising in professional journals
58
2011 ACCF Guideline Updates
p
Recommendations for Use of Dronedarone in Atrial Fibrillation
 ATHENA: Dronedarone ↓ risk of 1st CV hospitalization or death from any cause
bby 24% when
h comparedd to
t placebo
l b in
i patients
ti t with
ith paroxysmall or persistent
it t
AF/AFL who were > 70 years old.
N Engl J Med. 2009;360(7):668-78.
 ANDROMEDA: Dronedarone had > 2-fold mortality vs. placebo in patients
with severe heart failure.
N Engl J Med. 2008;358(25):2678-87.
 DIONYSOS: Dronedarone was less effective for maintenance of sinus rhythm
than amiodarone but better tolerated.
clinicaltrials.gov identifier: NCT00489736
 A meta-analysis
t
l i off 9 ttrials
i l evaluating
l ti dronedarone
d
d
or amiodarone
i d
concluded
l d d the
th same
as DIONYSOS trial: less efficacy but fewer side effects with dronedarone.
J Am Coll Cardiol. 2009;54(12):1089-95.
 For every 1
1,000
000 pts treated with dronedarone instead of amiodarone,
amiodarone it is estimated
59
that there will be ~228 more AF recurrences in exchange for 9.6 fewer deaths and 62
fewer adverse events requiring discontinuation of the drug.
Recommendation
Dronedarone is reasonable to decrease the need for hospitalization
for cardiovascular events in patients with paroxysmal AF or after
conversion of persistent AF. Dronedarone can be initiated during outpatient
Circulation. 2011;123(1):104-23.
therapy.
Dronedarone should not be administered to patients with class IV heart
failure or patients who have had an episode of decompensated heart
failure in the p
past 4 weeks, especiallyy if theyy have depressed left ventricular
function (LVEF < 35%).
Circulation. 2011;123(1):104-23.
Class
Level of
Evidence
IIa
B
III HARM
B
Class IIa: Benefit >> Risk “addt’l studies w/focused objectives needed; treatment is REASONABLE”
Cl III – Harm:
Class
“
“treatment
willll bbe hharmful
f l to patients””
Level B: Limited populations evaluated; data derived from a single RCT or nonrandomized studies
60
Sotalol
Sotalol
 Mechanisms of Action:
 Dose reductions required in renal impairment
 Contraindicated for treatment of AF when CrCl < 40 ml/min
 Increases the AV nodal refractory period
 DecreasesAV nodal conduction (K+ channel blockade)
 Proarrhyhthmic: Torsades de Pointes
 Non-selective beta-blocker
 Dose-dependent (caused by QT interval prolongation)
 Decreases HR, BP, myocardial contractility, myocardial oxygen demand,
bronchospasm

 Used to maintain normal sinus rhythm in AF
 Incidence
I id
ranges from
f
0.3
0 3 – 3.2%
3 2% depending
d
di on dosage
d
 Likelihood of proarrhythmia depends on patient characteristics
 Should not be used for pharmacologic cardioversion (can cause harm)
 It is possible for patients to require therapy with sotalol and a “pure”
pure

β-blocker concomitantly
 Sotalol SHOULD NOT be used in patients with systolic heart failure
(left ventricular dysfunction; EF < 35 – 40%)
61
Contraindicated if baseline QT interval > 450 msec
e.g.
g sex,, ppresence of heart failure,, renal function
 FDA-imposed restriction (Black Box Warning) that therapy be
initiated on inpatient basis to minimize risk of TdP (for telemetry &
e-lyte
l monitoring)
i i ) andd to have
h care available
il bl if TdP develops
d l
62
Dofetilide
Dofetilide
 Mechanism of action:
 Pure
P Class
Cl III antiarrhythmic:
ti h th i blockade
bl k d off K+ channel
h
l
 No effect on Na+ or adrenergic receptors
 Can be used for PCV and maintenance of NSR in AF
 IInitiation
i i i off therapy
h
contraindicated
i di d if baseline
b li QTc interval
i
l > 440 msec
 Initiation requires 12-lead ECG prior to first dose, then every 2 – 3 hours after
doses to monitor effect on QTc
 Risk of Torsades de Pointes (0.3 – 4.7%)
 Requires inpatient initiation on telemetry for at least 3 days!
 REMS (Risk Evaluation & Mitigation Strategy) Program [FDA]
 Dose reductions required in renal impairment
 Contraindicated in patients with CrCl < 20 ml/min
 Keep K+ > 4, Mg2+ > 2 prior to & during treatment with dofetilide
 Hospitals and individual practitioners have to be registered with Pfizer in order
to prescribe, stock, dispense, and/or initiate dofetilide
 TIPS (Tikosyn in Pharmacy System) Program


63
 Bee aware
awa e of
o potential
pote t a drug-drug
ug ug interactions!
te act o s!
Dofetilide is CONTRAINDICATED for use with:
Single mail-order pharmacy
Community pharmacies have to register with Pfizer to be able to stock & dispense
dofetilide
64
verapamil
hydrochlorothiazide
cimetidine (OTC!)
ketoconazole
prochlorperazine
trimethoprim
… and any drug that prolongs the QTc interval!
65
Accessed via http://www.tikosyn.com/Tikosyn_Treatment_Guidelines.html on 09/14/2010
Patient Case: Art B. Toofast
66
Accessed via http://www.tikosyn.com/Tikosyn_Treatment_Guidelines.html on 09/14/2010
Self-Assessment Q
Question #3
 Fast forward 6 months
Which of the following anti-arrhythmic agents would be
SAFE to use in a patient with CHF (EF = 15%) with an
estCrCl > 60 ml/min?
 Mr. Fastbeat is being considered for rhythm control therapy
because he remains symptomatic (DOE, near syncope,
fatigue) despite adequate rate control (resting HR 70’s-90’s)
a) Amiodarone + Dronedarone
b) Amiodarone
A i d
+ Dofetilide
D f ilid
c) Dofetilide + Dronedarone
d) Amiodarone + Sotalol
 Discuss potential options for this patient with CAD:
 Dofetilide, Dronedarone, Sotalol, Amiodarone
 BUN/SCr:
BUN/SC 16/0.9
16/0 9  est CrCl
C Cl 70 mL/min
L/
((using IBW)
 Baseline QTc = 460 msec
67
68
In Review: Treatment of AF
 Consideration of 3 issues:
 Prevention of thromboembolism
 Rate-control
 Rhythm-control
In Review: Treatment of AF
 Treatment of tachyarrhythmia
 AFFIRM trial:
 No difference in mortality for rate vs. rhythm groups
 Lower incidence of adverse effects and toxicities in rate group
 Rate-control:
 Stratify patients based on stroke risk, symptoms & co-morbidities
 Stroke
k risk:
k CHADS2 score + other
h kknown riskk ffactors ffor stroke
k
 -blockers, diltiazem, verapamil, digoxin
 1st line
li ffor patients
ti t with
ith new onsett atrial
t i l fibrillation
fib ill ti
 Rhythm-control:
 Warfarin, Dabigatran, ASA ± Clopidogrel
 Is the p
patient symptomatic?
y p
 palpitations, hypotension, fatigue, SOB, reduced exercise tolerance, angina
 DCCV and/or PCV +/- maintenance with AAD
 Remember: > 80% of thromboembolic events occur during the first 3 days after
cardioversion
 Consider co-morbidities:
 renall ffunction, respiratory d
disorders,
d
CHF
CHF, CAD
CAD, HTN
HTN, LVH
LVH, bbaseline
l QTc
QT intervall
69
 Consider for patients intolerant of rate
rate-control
control due to hypotension / bradycardia
70
 Consider for patients with disabling symptoms of AF
Activity:
y Antiarrhythmic
y
Top
p 10’s
Top 10 List: Amiodarone
 Break into 8 groups
 Each
E h group will
ill bbe given
i hhandouts
d
ffor one off the
h commonly
l
used antiarrhythmic drugs for the maintenance of NSR in AF
 The
Th task
t k for
f eachh group iis tto use your clinical
li i l experience
i
andd
the information provided in the handouts to come up with
The Top 10 Things A Pharmacist Should Know About ____”
“The
 The antiarrhythmics that will be covered:
 Amiodarone
 Dronedarone
 Dofetilide
 Sotalol
71
72
1
1.
6
6.
2.
7.
3.
8.
4.
9.
5.
10.
Top 10 List: Dronedarone
Top 10 List: Dofetilide
1
1.
6
6.
1
1.
6
6.
2.
7.
2.
7.
3.
8.
3.
8.
4.
9.
4.
9.
5.
10.
5.
10.
73
74
Top 10 List: Sotalol
Additional Resources
 ASHP initiative for improving clinical outcomes for patients with atrial
1
1.
6
6.
2.
7.
3.
8.
4.
9.
5.
10.
fibrillation. http://www.atrialfibrillationoutcomes.com/This
fibrillation
http://www atrialfibrillationoutcomes com/This website
has many resources available including recorded webinars that cover
ECG interpretation, management of atrial fibrillation, antiarrhythmic
drugs, and case-study based activities.
 Patient and caregiver
caregi er website:
ebsite www.stopafib.org
stopafib org
Look under “patient & caregiver resources” menu for helpful links for
both ppatients and pproviders.
 Video on pathophysiology of atrial fibrillation:
http://www.nhlbi.nih.gov/health/dci/Diseases/af/af_all.html
75
76
2011 ACCF Guideline Updates
Angina, h/o MI / CABG /
coronary stenting,
known coronary
atherosclerosis
th
l
i
Wall thickness > 1.4 cm
Measured via ECHO
LVEF
< 35-40%
Contraindications to Select Antiarrhythmic Agents
* Appropriate
antithrombotic therapy
should continue to be
provided indefinitely
based on individual risk
factors for stroke
51
Circulation. 2011;123(1):104-23.
Drug
est CrCl
(mL/min)
Baseline QT/QTc interval
(msec)
Amiodarone
n/a
n/a
Dronedarone
n/a
QTc > 500
Dofetilide
< 20
QTc > 440
Sotalol
< 40*
QT > 450