Download managing atrial fibrillation - Heart and Stroke Foundation

MANAGING ATRIAL FIBRILLATION:
BEYOND ANTICOAGULATION
Faculty: Peter Leong-Sit MD, MSc, FRCPC, FHRS
Associate Professor, Western University
Cardiologist, London Heart Rhythm Program
Relationships with commercial interests:
► Grants/Research Support: Bayer
► Consulting Fees: Medtronic, St. Jude Medical, Biosense-Webster
► Speaker Honoraria: Pfizer, Bristol-Myers-Squibb, BoehringerIngelheim, Bayer, Biosense-Webster, Medtronic
Potential for conflict(s) of interest:
► Bayer, Medtronic, Biosense-Webster, Pfizer, Bristol-MyersSquibb, Boehringer-Ingelheim develop and benefit from the sale
of products that might be discussed in this program.
Mitigating Potential Bias
►
►
►
►
►
All the recommendations involving clinical medicine are based on
evidence that is accepted within the profession.
All scientific research referred to, reported, or used is in the support or
justification of patient care.
Recommendations conform to the generally accepted standards.
The presentation will mitigate potential bias by ensuring that data and
recommendations are presented in a fair and balanced way.
Potential bias will be mitigated by presenting a full range of products that
can be used in this therapeutic area.
Outline
1. To review management strategies for atrial fibrillation
2. To identify good candidates for rhythm control or ablation for
atrial fibrillation
3. To provide an overview of atrial fibrillation ablation principles
4. To provide an overview of invasive options for stroke
prevention
Case #1: 66F with prior MI, otherwise healthy
• Cath: preserved LVEF, non-surgical
coronary disease
• No further CP since MI 3 years ago
• Frequent daily palpitations
• Meds: ASA, ramipril 5mg, bisoprolol
5mg, atorvastatin 40mg
Holter: Is this Atrial Fibrillation?
a) Yes
b) No
Is this Atrial Fibrillation?
a) Yes
b) No
Is this Atrial Fibrillation?
a) Yes
b) No
24-Hour Holter Monitor
• Predominant rhythm – sinus
• Salvos of AF lasting 15 seconds to 45 minutes
correlating with mild palpitations
• No conduction disease, AV block
• Mean rate = 80bpm [50-130bpm]
• Rates in AF = 90-120bpm
Outpatient AF Management
AF Management
Stroke
ASA
Warfarin
Dabigatran
Rivaroxaban
Apixaban
(LAA Occlusion)
Precipitating cause
Symptoms
Rate Control vs
Rhythm Control
Medical vs
Ablation
Back to our Case...
66F with paroxysmal AF
• Prior MI, preserved LVEF, no CHF
• Otherwise healthy
Would you recommend:
a) Nothing
b) ASA
c) Warfarin
d) NOAC
CHADS2 Score
• Combination of AFI and
SPAF schemes
• 1 Congestive Heart Failure
• 1 Hypertension
• 1 Age > 75 years
• 1 Diabetes Mellitus
• 2 Stroke or TIA
Score*
Stroke rate
0
1.9 (1.2 -3.0)
1
2.8 (2.0-3.8)
2
4.0 (3.1-5.1)
3
5.9 (4.6-7.3)
4
8.5 (6.3 -11.1)
5
12.5 (8.2-17.5)
6
18.2 (10.5-17.4)
*Score 0: Patients can be administered aspirin
*Score 1: Patients can be on aspirin or systemic anticoagulation
*Score ≥2: Patients should be on systemic anticoagulation
Gage BF, et al. JAMA. 2001;285:2864-2870.
CHA2DS2 VASc Score
• Score 0/9 = 0 thromboembolic events
• Score 1/9 = 0.6% (0.0 – 3.4%)
• Score 2/9 = 1.6% (0.3 – 4.7%)
Lip GY et al. Chest. 2010 Feb;137(2):263-72.
Back to our Case...
66F with newly diagnosed AF
• No hypertension, diabetes, no prior CHF or
stroke but prior MI
Hence, CHADS2 score = 0
But CHA2DS2-VASc score = 3!
2016 AF Guidelines
Macle L. et al. Can J Cardiol 2016;32:1170-85.
Back to our Case...
66F with newly diagnosed AF
• No hypertension, diabetes, no prior CHF or stroke
but prior MI
Hence, CHADS2 score = 0
But CHA2DS2-VASc score = 3!
Current Canadian guidelines:
• Over age 65, therefore anticoagulate
Summary of Approach
• Any patient above age 65 with AF should have systemic
anticoagulation
• Below age 65 with CHADS2 risk factors should have systemic
anticoagulation
• Below age 65 with vascular disease, ASA is recommended
• Below age 65 with no vascular disease, nothing is
recommended
Which to Choose?
• Is warfarin ok for my patient?
– Mechanical valve …. definitely warfarin
– Excellent INRs (TTR > 70%) may limit benefits of switching
• Renal Function / Liver Metabolism
– Poor renal function (GFR < 30-50)
– Apixaban, rivaroxaban > dabigatran
– GFR < 15 .... definitely warfarin
• Compliance of Once daily vs Twice daily
– No monitoring of compliance
2014/2016 Canadian AF Guidelines
• Emphasis is on choosing the new agents over
warfarin rather than choosing between the new
agents
• Warfarin based on RCT data < 6600 pts
• New agents tested in > 70,000 pts
Verma et al. Can J Cardiol 2014;30:1114-30.
Macle et al. Can J Cardiol 2016;32:1170-85.
Limited Use Coverage
Clinical Criteria
1) Failed warfarin trial
> 2 months
> 35% INRs outside therapeutic range
2) Warfarin contraindicated or inability to monitor INRs
Limited Use Codes
• Dabigatran = 431
• Rivaroxaban = 435
• Apixaban = 448
WHAT ABOUT BLEEDING RISK?
Patient Preferences
Lahaye S et al. Thromb Haemost. 2013 Dec 12;111(4)
Mortality after major bleed: 5 Phase III trials
Mortality rate (%)
0.2
Warfarin
Dabigatran
0.1
0.3
0
5
10
15
20
Time (days)
25
30
35
The Kaplan–Meier analysis indicated a reduced risk for death with
dabigatran* vs warfarin during 30 days from the bleeding (P=0.052)
Majeed A. et al. Management and Outcomes of Major Bleeding on Dabigatran or Warfarin, American Society of Hematology Conference , Atlanta, GA, Dec 2012
24
Dec 2012
Remember: There is Harm in Inaction
Dual antiplatelet therapy
3%
Single
antiplatelet agent
15%
No antithrombotics
25%
18%
Warfarin
therapeutic
Warfarin
subtherapeutic
39%
82% of AF patients with a 2nd stroke not anticoagulated
Gladstone DJ, et al. Stroke 2009;40:235-240
Case #2: 82F with persistent AF
• Problem List:
– Hypertension, Diabetes, Dylipidemia
– Post-partum DVT with a PE
– L. breast Ca with mastectomy 2010
• CHADS = 3, CHADS-VASc score = 4
• On warfarin, suffered large GI bleed
What is the next step?
a) Continue warfarin
b) Stop warfarin, start ASA
c) Stop warfarin, start NOAC
d) Stop warfarin, refer for LA appendage
closure
Case #2
• Endoscopy: reactive gastropathy and
vascular ectasias
• Switched to Rivaroxaban 20mg daily,
recurrent GI bleed
• Switched to Apixaban 2.5mg bid,
recurrent GI bleed
Mechanism of Stroke in AF
Slow-moving blood that “pools”…
… can form clot in
the LAA, which can
embolize and result
in Stroke
Approved Percutaneous Options
• Amplatzer Cardiac Plug (SJM)
• Watchman device (BSx)
The Watchman Left Atrial Appendage Closure Device
During Endothelialization:
Warfarin for 45 days
ASA / Plavix for 6 months (TEE)
ASA alone
Maisel W. N Engl J Med 2009
Meta-Analysis Shows Comparable Primary
Efficacy Results to Warfarin
HR
p-value
0.79
0.22
1.02
0.94
Ischemic stroke or SE
1.95
0.05
Hemorrhagic stroke
0.22
0.004
Ischemic stroke or SE >7 days
1.56
0.21
0.48
0.006
All-cause death
0.73
0.07
Major bleed, all
1.00
0.98
Major bleeding, non procedure-related
0.51
0.002
Efficacy
All stroke or SE
CV/unexplained death
Favors WATCHMAN 
0.01
0.1
1
Hazard Ratio (95% CI)
 Favors warfarin
10
Source: Holmes DR, et al. Holmes, DR et al. JACC 2015; In Press. Combined data set of all PROTECT AF and PREVAIL WATCHMAN patients versus chronic warfarin patients
Who should be considered?
1. Major bleeding while taking anticoagulation
therapy
2. Inability to maintain stable INR and not a NOAC
candidate
3. CVA/TIA despite therapeutic warfarin or NOAC
AF Stroke Prevention Key Points
• Remember CHADS65 risk score
• NOACs preferred over warfarin
• NOACs contraindicated in mechanical
valves and severe renal failure
• LAA closure is not a replacement for
anticoagulation, but can be considered in
refractory cases
Outpatient AF Management
AF Management
Stroke
ASA
Warfarin
Dabigatran
Rivaroxaban
Apixaban
(LAA Occlusion)
Precipitating cause
Symptoms
Rate Control vs
Rhythm Control
Medical vs
Ablation
HOW DO I DECIDE BETWEEN RATE
VS RHYTHM CONTROL?
Case #3: 57M with lone paroxsymal AF
• Severe palpitations 1-3x/month, up to 45 minutes
• Problem List: mild asthma, solitary kidney with Cr 150
AF with HR = 110bpm
How should the AF be treated?
a) Metoprolol 25mg BID
b) Diltiazem 120mg daily
c) Digoxin 0.125mg daily
d) Amiodarone 200mg daily
Medical Options 101
• AVN blocking agents – SLOW the AF
– Beta-receptor antagonist
– Ca-channel blockers
– Digoxin
• Anti-arrhythmic agents – STOP the AF
– Class I: Propafenone, Flecainide
– Class III: Sotalol, Dronedarone, Amiodarone
AFFIRM
• Primary endpoint: All cause mortality
– N=4,060
– No difference between two groups
– Trend to better survival in rate control group after 1.5-2 years
• Secondary endpoints
– functional status
– QOL
– ischemic strokes
AFFIRM Investigators NEJM 2002;347:1825
No difference
Back to Case
• Young patient with lone PAF
• Key issue is symptom control
• Symptoms during AF are poorly ratecontrolled (110bpm)
• Always start with an AVN blocking agent
Follow-up Visit
• Patient now on diltiazem 360 mg bid
• Sinus rates now 50 bpm
• Repeat Holter:
– AF episodes still recurrent, but associated with
heart rate of 70-90 bpm
What is the next step?
a) The AF is well rate-controlled...
Continue current management
b) The AF is still recurrent... Add digoxin
c) The AF is still recurrent... Change to an
antiarrhythmic medication
d) I don’t know
Remember what we are doing…
AF Management
Stroke
ASA
Warfarin
Dabigatran
Rivaroxaban
Apixaban
(LAA Occlusion)
Precipitating cause
Symptoms
Rate Control vs
Rhythm Control
Medical vs
Ablation
I TRIED AVN AGENTS AND THE
PATIENT STILL FEELS AWFUL. NOW
WHAT?
Why Rhythm Control?
No Symptoms
Symptoms
• Primary evidence-based efficacy is improvement in
symptoms
• Rhythm control should NOT be performed to:
– Reduce stroke risk
– Discontinue systemic anticoagulants
– Make the ECG or Holter look better
Back to Case...
• Patient is referred to cardiology / EP
specialist
• They are started on an antiarrhythmic
medication
• What do I need to know?
Anti-arrhythmic Drug Options
• Four predominant anti-arrhythmics for rhythm
control of AF
1. Propafenone
2. Flecainide
(Class I AADs)
3. Sotalol
4. Amiodarone
(Class III AADs)
Anti-arrhythmic Basics
• Flecainide/Propafenone
– Requires adjunct AVN blocking agent
– Contraindicated in heart disease
– Can widen the QRS or cause VT
• Typical doses:
– Flecainide 50mg bid - 150mg bid
– Propafenone 75mg bid/tid - 300mg tid
Anti-arrhythmic Basics
• Sotalol
– Already has AVN blocking properties
– Can be used as single agent
– Dosing 80mg bid - 160mg bid
• Risk of Torsades de Pointes
– Contraindicated in Long QT or renal failure
– Cautious with elderly, females
– Repeat ECG in 1 wk for QT prolongation
Anti-arrhythmic Basics
• Amiodarone
–
–
–
–
Already has AVN blocking properties
Can be used as single agent
Loading dose: 10g load (400mg bid/tid)
Maintenance dose: 200mg daily
• Requires monitoring for side effects
– TSH, liver tests every 6 months
– CXR every year, baseline PFT
– Ophthalmology, CT chest if symptoms
Pill-In-The-Pocket Approach
• Flecainide 200-300mg x 1 PRN
• Propafenone 450-600mg x 1 PRN
AAD Strategy
Depends on episode frequency & duration
Rare
Infrequent
Weekly
Days
Hours
Minutes
Pill-In-Pocket
Maintenance
Back to Case...
• Sotalol was started and up-titrated
– Symptoms continued
• Patient was switched to Amiodarone
and is feeling better
• Is he going to be considered for
cardiac ablation?
AF Invasive Options
Invasive Rate Control
• AV node ablation (99% success)
(with pacemaker implantation)
Invasive Rhythm Control
• Atrial flutter ablation (95% success)
• Atrial fibrillation ablation (50-80% success)
AV Node Ablation and Pacemaker
• Causes complete AV block
• Atria continue to fibrillate
• Pacemaker controls HR
• Must remain on anticoagulation
• “Ultimate” rate-control strategy
• 99% success
• 1% risk
What about rhythm control?
• Contrast Aflutter and Afib
Easier to rhythm control
Harder to rate control
Simple ablation 95% success
Low risk 1-2%
Difficult to rhythm control
Easier to rate control
Complex ablation 50-80% success
Higher risk 3-4%
Atrial Flutter
•Counterclockwise
right atrial reentry
Atrial Flutter Ablation
Ablation of the
cavo-tricuspid
isthmus (CTI)
Predictable circuit
Small lesion set
“First-line” therapy
AFib Electrophysiology
Chaotic
disorganized
rhythm
Pulmonary Vein Ectopy
Transseptal Approach
Asirvatham SJ. Heart Rhythm 2007;4(4)
Fencing off all 4 Veins
Success rates for
paroxysmal AF is
70-80%
Still requires
anticoagulation
First-line Rhythm Control?
Which patients should I refer early?
** Atrial flutter
Kerr C, Roy D. Can J Cardiol 2004.
Stroke Take-Home Points
• Use CHADS65 risk stratification
• NOAC preferred over warfarin
• For those who have a true anticoagulation
contraindication, consider LAA closure
Symptom Take-Home Points
• For symptomatic atrial fibrillation, start with rate
control for most
• Refer if still symptomatic for initiation of
anti-arrhythmic medications or catheter ablation
• Rhythm control has little role for minimally
symptomatic patients
– Rhythm control does not reduce stroke risk
Backup Slides
Left Atrial Appendage
Watchman FDA Approved – March 2015
Case 1: 66M Neurologist
• Mild hypertension – sometimes takes meds
• Has infrequent paroxysmal AF
– Couple of hours at a time twice per year
– Takes beta-blocker and waits it out
• Takes Rivaroxaban (may not be reliably)
• Avid cyclist and alpine skier
– Skips his rivaroxaban when active
• Wants to explore options to replace OAC
Implantation
•
•
•
•
TEE-guided under general anesthesia
1-2 hour procedure
Overnight stay
Follow-up TEEs at 1, 3, and 6 months
• When able, use of dual antiplatelet (ACP) or
short-term warfarin (Watchman) postprocedure
The Watchman Left Atrial Appendage Closure Device
During Endothelialization:
Warfarin for 45 days
ASA / Plavix for 6 months (TEE)
ASA alone
Maisel W. N Engl J Med 2009;10.1056/NEJMp0903763
Device Healing
2 day
1 month
2 week
3 month
Nakai T. et al. Circulation 2002;105:2217
Meta-Analysis Shows Comparable Primary
Efficacy Results to Warfarin
HR
p-value
0.79
0.22
1.02
0.94
Ischemic stroke or SE
1.95
0.05
Hemorrhagic stroke
0.22
0.004
Ischemic stroke or SE >7 days
1.56
0.21
0.48
0.006
All-cause death
0.73
0.07
Major bleed, all
1.00
0.98
Major bleeding, non procedure-related
0.51
0.002
Efficacy
All stroke or SE
CV/unexplained death
Favors WATCHMAN 
0.01
0.1
1
Hazard Ratio (95% CI)
 Favors warfarin
10
Source: Holmes DR, et al. Holmes, DR et al. JACC 2015; In Press. Combined data set of all PROTECT AF and PREVAIL WATCHMAN patients versus chronic warfarin patients
SH-230506-AD June15
Ischemic Stroke Risk
(Events/100 PatientYears)
WATCHMANTM Device Reduced
Ischemic Stroke Over No Therapy
8
7
6
5
4
3
2
1
0
79%
67%
83%
Relative
Reduction
Relative
Reduction
Relative
Reduction
PROTECT
AF
Baseline
CHA2DS2-VASc = 3.4
PREVAIL
Only
Baseline
CHA2DS2-VASc = 3.8
Imputed Ischemic
Stroke Rate*
CAP
Baseline
CHA2DS2-VASc = 3.9
* Imputation based on published rate with adjustment for CHA2DS2-VASc score (3.0); Olesen JB. Thromb Haemost (2011)
FDA Oct 2014 Panel Sponsor Presentation. Hanzel G, et al. TCT 2014 (abstract)
SH-230506-AD June15
WHAT DO I USE?
I am comfortable with warfarin.
I’m still not sure about the NOACs.
Warfarin for AF Stroke Prevention
Adjusted dose warfarin compared
with placebo or control
AFSAK I
SPAF I
BAATAF
CAFA
SPINAF
EAFT
All trials (n = 6)
AFSAK I = Copenhagen Atrial Fibrillation, Aspirin and Anticoagualtion Study
SPAF I = Stroke Prevention in Atrial Fibrillation Study
BAATAF = Boston Area Anticoagulation Trial doe Atrial Fibrillation
CAFA = Canadian Atrial Fibrillation Anticoagulation
SPINAF = Stroke Prevention in Nonrheumatic Atrial Fibrillation
EAFT = European Atrial Fibrillation Trial
Hart RG et al. Ann Intern Med 2007;146:857-867
Meta-analyses of antithrombotic therapies
Comparison
No. trials
No. pts
RRR stroke 95%
CI
Adjusted–dose warfarin vs control
6
2900
64%
(49,74)
Antiplatelets vs control
8
4876
22%
(6,35)
Adjusted–dose warfarin vs antiplatelets
12
12,963
39%
(27,49)
Hart RG and Aguilar MI. J Thromb Thrombolysis 2008;25:26–32
Limitations of Warfarin Therapy
Unpredictable response
Frequent dose
adjustments
Narrow therapeutic
window
Numerous food-drug
interactions
Routine coagulation
monitoring
Slow onset/offset
of action
Limitations of
Warfarin
Numerous drug-drug
interactions
Warfarin resistance
Ansell J et al. Chest 2008; Umer Ushman MH et al. J Interv Card
Electrophysiol 2008; Nutescu EA et al. Cardiol Clin 2008
Inadequate anticoagulation!
Mean Time in Therapeutic Range = 64%
Remember: target INR is 2.5 (not 2.0)
Connolly SJ, et al. N Engl J Med 2009;361:1139-1151
We do a really poor job with warfarin!
Dual antiplatelet
therapy
Single
antiplatelet agent
3%
Preadmission meds in patients with known
AF and a prior CVA/TIA admitted with
acute CVA (N=323)
No antithrombotics
15%
25%
18%
Warfarin
subtherapeutic
Warfarin
therapeutic
39%
Gladstone DJ, et al. Stroke 2009;40:235-240
NOAC Major RCTs
1 Connelly SJ et al, NEJM 2009; 361:1139-51
2 Patel MR et al, NEJM 2012; 365:883-91
3 Granger, J MD. NEJM 2012;365:981-92
All NOACS: Stroke or SEE
Risk Ratio (95% CI)
RE-LY
0.66 (0.53 - 0.82)
ROCKET AF
0.88 (0.75 - 1.03)
ARISTOTLE
0.80 (0.67 - 0.95)
ENGAGE AF-TIMI 48
0.88 (0.75 - 1.02)
Combined
0.81 (0.73 - 0.91)
[150 mg]
[60 mg]
[Random Effects Model]
N=58,541
0.5
Heterogeneity p=0.13
p=<0.0001
Favors NOAC
1
Favors Warfarin
2
Ruff CT, et al. Lancet 2013 [in-press]
ANY DIFFERENCES BETWEEN THE
NEW AGENTS?
New Oral Anticoagulants:
Pharmacology
Apixaban
Dabigatran
Rivaroxaban
Direct factor Xa
inhibitor
Direct thrombin
inhibitor
Direct factor Xa
inhibitor
Renal excretion
~ 27%
~ 85%
~ 33%
Half-life (hours)
~ 12 h
~ 12−14 h
~ 5−13 h
INR monitoring
Not required
Not required
Not required
Action
ELIQUISTM (apixaban). PM, 2012. Bristol-Myers Squibb/Pfizer Canada.
PRADAXTM (dabigatran). PM, 2012. Boehringer Ingelheim Canada Ltd.
XARELTO® (rivaroxaban). PM, 2012. Bayer Canada.
New Oral Anticoagulants:
Evidence-Based Medicine
Trials
Number of
participants
CHADS2 score
Dose
Dose adjustment
Apixaban
Dabigatran
Rivaroxaban
ARISTOTLE
RE-LY
ROCKET AF
18 201
18 113
14 262
2.1
2.2
3.5
5 mg BID
2.5 mg BID
150 mg BID
110 mg BID
20 mg OD
15 mg OD
2.5 mg BID if 2/3 criteria:
age ≥ 80, weight ≤ 60
kg,
or creatinine
≥ 133 μmol/L
110 mg BID if
age ≥ 80 or age
≥ 75 with a risk factor
for bleeding
15 mg OD if CrCl
30−49 ml/min
ELIQUISTM (apixaban). PM, 2012. Bristol-Myers Squibb/Pfizer Canada.
PRADAXTM (dabigatran). PM, 2012. Boehringer Ingelheim Canada Ltd.
XARELTO® (rivaroxaban). PM, 2012. Bayer Canada.
AUC ratio vs. Normal
Renal Function
Effect of Renal Dysfunction
7
6
5
4
3
2
1
0
Rivaroxaban
Dabigatran
Normal
Mild Renal
Moderate Severe Renal
Impairment
Renal
Impairment
Renal
Function
(50–79
Impariment (<30 mL/min)
(≥80 mL/min) mL/min)
(30–49
mL/min)
RCT data on adjusted dose for CrCl 30-49 for Rivaroxaban
but not for Dabigatran
Kubitza et al. Br J Clin Pharmacol. 2010 Nov;70:703
Boehringer Ingelheim Advisory Committee Briefing Document
Once-Daily vs BID Dosing
Adherence (%)
P<.01
100
80
93.1 86.2
P<.01
84.9
P<.01
73.8
60
76.3
50.4
40
20
0
Taking
Adherence
Regimen
Adherence
Dosing Frequency
Once-daily
Twice-daily
Timing
Adherence
Coleman CI et al. Curr Ned Res Opin. In press.
ANYTHING ELSE NEW IN THE
2016 GUIDELINES?
Large Focus on CAD plus AF
Macle L. et al. Can J Cardiol 2016;32:1170-85.
Post-PCI
Macle L. et al. Can J Cardiol 2016;32:1170-85.
Post-AMI
Macle L. et al. Can J Cardiol 2016;32:1170-85.
SO WHO SHOULD NOT BE ON A
NEW AGENT?
Patients Unsuitable for New Agents
• Patients with mechanical valves
• Patients with advanced renal disease
(CrCl<15-30 mL)
• Patients with active bleeding
Pradax Product Monograph, 2010, Boehringer Ingelheim Canada Ltd
Pradaxa Prescribing Information 2011, Boehringer Ingelheim Pharmaceuticals Inc, USA
Fuster V et al. J Am Coll Cardiol 2006;48;854-906
Advanced Age
• Efficacy and safety of new agents no different >75
vs <75 yrs age
• The new agents have a lower intracranial bleed
rate than warfarin
• Suggest lower dose when >75-80 yrs