Afib and Stroke Prevention Update

DR JOSE OSORIO
Atrial Fibrillation
Update on Stroke Prevention
www.theafibclinic.com

The estimated US prevalence of atrial fibrillation (AF) in the year 2050 ranges from 5.6 million to
as high as 15.9 million individuals.
Jared W. Magnani et al. Circulation. 2011;124:1982-1993
Atrial Fibrillation
An Epidemic

0
5
10
15
20
25
30
35
50-59 60-69 70-79 80-89
3000838-7
%
Percent of Total Strokes
Attributable to Atrial Fibrillation
Stroke 22(18), 1991
• 500,000 strokes/year in U.S.
• Up to 20% of ischemic strokes occur in
patients with atrial fibrillation

AF increases Risk and Stroke Severity
• 1061 patients admitted with acute
ischemic stroke
– 20.2% had AF
• Bedridden state
– With AF 41.2%
– Without AF 23.7%
• Odds ratio for bedridden state following stroke due to AF
2.23 (95% CI, 1.87-2.59; P<.0005)
P<.0005
Dulli et al. Neuroepidemiology. 2003;22:118-123.
Atrial Fibrillation
Stroke Risk

Atrial Fibrillation
Stroke Pathology
3000838-9
Blackshear: Ann Thoracic Surg 61, 1996
Johnson: Eur J Cardiothoracic Surg 17, 2000
Fagan: Echocardiography 17, 2000
• Insufficient contraction of LA and LAA leads to
stagnant blood flow
• Most likely culprit:
• Embolization of LAA clot
• 90% of thrombus found in LAA
• TEE-based risk factors
• Enlarged LAA
• Reduced inflow and outflow velocities
• Spontaneous Echo contrast

• >90% of strokes in AF
patients are secondary
to LAA emboli

Atrial Fibrillation
Stroke Risk
Assessment

Risk Factor Score
CHF 1
Hypertension 1
Age > 75 1
Diabetes 1
Stroke/TIA 2
Vascular disease
(MI,PVD)
1
Age 65-74 1
Sex Category Female 1
Atrial Fibrillation
Stroke Risk Assessment
CHADS2 VASc Score

ESC Guidelines 201
Atrial Fibrillation
CHADS2 VASc Score
Stroke Rate

ESC Guidelines 201
AtrialFibrillation
CHADS2 VASc Score – Why use it?
Helps distinguishlow risk patients

Atrial Fibrillation
Stroke Prevention
• CHADS2Vasc
– 0 – no antithrombotic therapy
– 1 – no therapy, Aspirin or anticoagulant
– 2 or greater – oral anticoagulation
Lone Afib
Score: 0
Stroke Risk: <1%
Persistent Afib
 Diabetes/ Hypertension/ Age
Score: 3
Stroke Risk: 4%

Atrial Fibrillation
Stroke Prevention
Medical Therapy

• Aspirin:
– No data for low risk patients
– Dual therapy can significantly increase risks of bleeding
– If revascularization/CAD indication
• Consider BMS
• Dual therapy: clopidogrel, no aspirin
Atrial Fibrillation and Stroke Prevention
Medical Therapy - Aspirin

Warfarin
3000838-10
Cooper: Arch Int Med 166, 2006
Lip: Thromb Res 118, 2006
• Warfarin still widely used
• Assuming 51 ischemic strokes/1000 pt-yr
• Warfarin prevented 28 strokes at expense of 11
fatal bleeds
• Aspirin prevented 16 strokes at expense
of 6 fatal bleeds
• Time in therapeutic window is low even in clinical
trials
• Discontinuation
• Complications

• NOACs
– Dabigatran
– Apixaban
– Rivaroxaban
– Edoxaban
• Guidelines
– Novel anticoagulants were added to warfarin as preferred
therapy.
– First line therapy
– Preferred therapy for patients with labile INR
NOACs

Large NOAC Trials

Possible drug-drug interactions
Dabigatran Apixaban Edoxaban Rivaroxaban
Atorvastatin P-gp/ CYP3A4 +18% no data yet no effect no effect
Digoxin P-gp no effect no data yet no effect no effect
Verapamil P-gp/ wk CYP3A4
+12–180%
no data yet
+ 53% (slow release)
minor effect
Diltiazem P-gp/ wk CYP3A4 no effect +40% No data minor effect
Quinidine P-gp +50% no data yet +80% +50%
Amiodarone P-gp +12–60% no data yet no effect minor effect
Dronedarone P-gp/CYP3A4 +70–100% no data yet +85% no data yet
Ketoconazole;
itraconazole;
voriconazole;
posaconazole;
P-gp and BCRP/
CYP3A4
+140–150% +100% no data yet up to +160%
19
www.escardio.org/EHRA
Red – contraindicated; orange – reduce dose; yellow – consider dose reduction if another yellow factor present;
hatching – no data available; recommendation made from pharmacokinetic considerations

Interaction Dabigatran Apixaban Edoxaban Rivaroxaban
Fluconazole CYP3A4 no data no data no data +42%
Cyclosporin;
tacrolimus
P-gp no data no data no data +50%
Clarithromycin;
erythromycin
P-gp/ CYP3A4 +15–20% no data no data +30–54%
HIV protease
inhibitors
P-gp and BCRP/
CYP3A4
no data strong increase no data up to +153%
Rifampicin;
St John’s wort;
carbamezepine;
phenytoin;
phenobarbital
P-gp and BCRP/
CYP3A4/CYP2J2
-66% -54% -35% up to -50%
Antacids GI absorption -12-30% no data no effect no effect
20
Red – contraindicated; orange – reduce dose; yellow – consider dose reduction if another yellow factor present;
hatching – no data available; recommendation made from pharmacokinetic considerations
Possible drug-drug interactions

NOACs in renal dysfunction
Dosing in chronic kidney disease
Dabigatran Apixaban Edoxaban * Rivaroxaban
Note: 75 mg BID approved in US
only **
-if CrCl 15-30 ml/min
- if CrCl 30-49 ml/min
-and other orange factor (e.g.
verapamil)
CrCl 15-29 ml/min: 2.5 mg
BID
Serum creatinine ≥ 1.5 mg/dl
in combination with age ≥80
years or weight ≤60 kg
(SmPC) or with other yellow’
factor: 2.5 mg BID
not available 15 mg OD when CrCl
15-49 ml/min
28
1. Camm et al, Eur Heart J 2012;33:2719-47

Study NOAC VKA Outcome
RE-LY Dabigatran
3.3%
Warfarin
3.6%
RR 0.93
95% CI 0.81-1.07
P = 0.31
ARISTOTLE Apixaban
2.1%
Warfarin
3.1%
HR 0.69
95% CI 0.60-0.8
P = < 0.001
ROCKET-AF Rivaroxaban
5.6%
Warfarin
5.4%
HR 1.04
95% CI 0.90-1.20
P = 0.58
Large NOAC Trials – Major Bleeding

Study NOAC VKA Outcome
RE-LY Dabigatran
0.3%
Warfarin
0.7%
RR 0.40
95% CI 0.27-0.60
P= <0.001
ARISTOTLE Apixaban
0.3%
Warfarin
0.8%
HR 0.42
95% CI 0.30-0.58
P = <0.001
ROCKET-AF Rivaroxaban
0.5%
Warfarin
0.7%
HR 0.67
95% CI 0.47-0.93
P = 0.02
Large NOAC Trials – Intracranial Hemorrhage

• Easier to use
• Predictable effect without need for monitoring
– more predictable half-life/elimination  surgery
• Fewer food and drug interactions
• Caution when CKD
• Improved efficacy/safety ratio
– But bleeding risk also exists
– WARFARIN BLEEDING IS UNDER/NOT REPORTED
• Reversal Agents
– Available for pradaxa
Large NOAC Trials – Intracranial Hemorrhage

Atrial Fibrillation
Left Atrial Appendage
Closure

Patient’s choice
Challenges with OAC
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1 2 3 4 5 6
CHADS2 Score
p < 0.001
(n=27,164)
AFPatientsUsing
Anticoagulation
Anticoagulation Use Declines
with Increased Stroke Risk1

 Less than 50% of patients eligible are being
treated with OACs
 Risk of bleeding
 GI bleeding
 Hemorrhagic Strokes
 Contraindications for anticoagulants:
 Bleeding
 Hemorrhagic Stroke
 Frequent Falls
 low Platelet Count
 Recent Surgery
Patient’s choice
Challenges with OAC

High Risk (>4%/year) >4
Moderate Risk (2-4%/year) 2-3
Low Risk (<2%/year) 0-1
HAS-BLED

LAA Closure

LAA Closure – Watchman Device
Canine Model – 30 Day
Canine Model – 45 Day
Human Pathology - 9 Months Post-implant
(Non-device related death)

Watchman Device - Trials
PROTECT
AF
CAP
Registry
PREVAIL CAP2
Registry Totals
Enrollment 2005-2008 2008-2010 2010-2012 2012-2014
Enrolled 800 566 461 579 2406
Randomized 707 --- 407 --- 1114
WATCHMAN:
warfarin (2:1)
463 : 244 566 269 :138 579
1877:
382
Mean Follow-up
(years)
4.0 3.7 2.2 0.58 N/A
Patient-years 2717 2022 860 332 5931

Watchman Device - Trials
Characteristic
PROTECT
AF
N=707
CAP
N=566
PREVAIL
N=407
CAP2
N=579 p-value
CHADS2 Score 2.2 ± 1.2 2.5 ± 1.2 2.6 ± 1.0 2.7 ± 1.1 <0.0001
CHADS2 Risk Factors (% of Patients)
CHF 26.9 23.3 19.1 27.1 0.004
Hypertension 89.8 91.4 88.8 92.5 0.15
Age ≥ 75 43.1 53.6 51.8 59.7 <0.001
Diabetes 26.2 32.4 24.9 33.7 0.001
Stroke/TIA 18.5 27.8 30.4 29.0 <0.0001
CHA2DS2-VASc 3.5 ± 1.6 3.9 ± 1.5 4.0 ± 1.2 4.5 ± 1.3 <0.0001

Watchman – Implant Success
p = 0.04
Study 45-day 12-month
PROTECT AF 87% >93%
CAP 96% >96%
PREVAIL 92% >99%
Implant success defined as deployment and release of the device into the left atrial appendage
Warfarin Cessation PREVAIL Implant
Success
No difference between new
and experienced operators
Experienced Operators
• n=26
• 96%
New Operators
• n=24
• 93% p = 0.28
PROTECT AF and CAP: Reddy, VY et al. Circulation. 2011;123:417-424.
PREVAIL: Holmes, DR et al. JACC 2014; 64(1):1-12.

Watchman – Complications
9.9%
4.8%
4.1% 4.1% 3.8%
0.0%
2.0%
4.0%
6.0%
8.0%
10.0%
12.0%
CAP PREVAIL CAP2
Patients
with
Safety
Event
(%)
PROTECT AF
1st Half 2nd Half
n=232 n=231 n=566 n=269 n=579
All Device and/or procedure-related serious adverse events within 7 Days
Learning
Curve
~50% New Operators
in PREVAIL
Source: FDA Oct 2014 Panel Sponsor Presentation.

Protect AF trial – Bleeding Risk
50
60
70
80
90
100
0 7
Time (months)
Free of
Major
Bleeding
Event
(%)
6 6046 1808 45
Time (days)
Warfarin
+Aspirin
Warfarin
+Aspirin
Aspirin+
Clopidogrel
Aspirin
WATCHMAN
Warfarin
Definition of bleeding: Serious bleeding event that required intervention or hospitalization according to adjudication committee
71%
Relative Reduction
In Major Bleeding
after cessation of
anti-thrombotics
HR = 0.29
p<0.001
WATCHMAN
Device Arm Drug
Protocol
Price, MJ. Avoidance of Major Bleeding with WATCHMAN Left Atrial Appendage Closure Compared with Long-Term Oral Anticoagulation : Pooled Analysis of the PROTECT-AF
and PREVAIL RCTs. TCT 2014 (abstract)

Watchman Trials Meta Analysis
HR p-value
Efficacy 0.79 0.22
All stroke or SE 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
CV/unexplained death 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
0.01 0.1 1 10
Favors WATCHMAN   Favors warfarin
Hazard Ratio (95% CI)
Holmes, DR et al. JACC 2014www.theafibclinic.com

Subgroup Analysis
Subgroup p-value
Age
< 75
0.910
> 75
Sex
Female
0.679
Male
CHADS2
Score
≤ 3
0.758
>3
CHA2DS2-
VASc Score
≤ 4
0.271
>4
HAS-BLED
≤ 2
0.098
>2
History of TIA
Stroke
No
0.623
Yes
0.1 1.0 10.0
Hazard Ratio
Favors WATCHMAN   Favors warfarin
Holmes, DR et al. JACC 2014www.theafibclinic.com

Summary
• WATCHMAN comparable to warfarin for primary efficacy
(HR=0.79)
– Results maintained when all 4 studies were analyzed
– Results consistent across subgroups
• Significant reductions in
– CV mortality
– Hemorrhagic strokes
– Major bleeding post procedure
• Safe alternative to long term OAC
• Significant improvement in quality of life

Conclusion
• Afib burden continues to increase
– Prevelance
– Stroke risk and severity
• NOACs are preferred over warfarin
– Efficacious
– More convenient for patients
– Bleeding still a risk for all oral anticoagulants
• Left atrial appendage closure
– Safe alternative
– Specially advantageous for patients with high bleeding risk

Afib and Stroke Prevention Update

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