Direct Oral Anticoagulant Use in Valvular Atrial Fibrillation
September 14, 2018
Nina Maguire, PharmD
PGY1 Pharmacy Resident
Seton Healthcare Family
9/7/2018
1
ASCENSION TEXAS
Nina Maguire, PharmD
PGY-1 Pharmacy Resident, DSMC-UT
September 14, 2018
Direct Oral Anticoagulant (DOAC) Use in
Atrial Fibrillation with Valvular Heart
Disease
• No conflicts of interest to disclose
2
Disclosures
1. Understand the multiple definitions of valvular atrial
fibrillation and the thromboembolic risk associated with
valvular dysfunction.
2. Summarize the evidence for the use of DOACs in
various valvular heart disease patient populations.
3. Apply DOAC study results to the clinical setting in
anticoagulation decision making for patients with valvular
atrial fibrillation.
3
Objectives
RR is a 67 year old male presenting to clinic with a new diagnosis of atrial fibrillation. Past medical history is significant for bioprosthetic mitral valve (placed 2013), hypertension, and gout. Patient also has a history of alcohol abuse and has a baseline INR of 1.3.
Which of the following anticoagulants is the most appropriate therapy for RR?
A. Warfarin
B. Enoxaparin
C. Apixaban
D. Rivaroxaban
4
Meet the patient…
5
Background
• Estimated up to 6.1 million people in the US have atrial
fibrillation (AF)
• Number of patients with AF is expected to double over the
next 25 years
• AF increases the risk for ischemic stroke fivefold
• 750,000 hospitalizations and 130,000 deaths per year
6
Atrial fibrillation
January CT, et al J Amer Col Card. 2016;64(21):2246-80.
Feinberg WM, et al Arch Intern Med. 1995;155(5):469-73.
Agen Healthcare Research and Quality. 2012.
9/7/2018
2
7
Role of structural heart disease in AF
Iwasaki Y et al. Circulation. 2011:124:2264-74.
Vaziri S, et al. Circulation. 1994:89(2):724-30.
• AF commonly occurs in patients with structural heart
disease
- Heart failure, valvular heart disease, coronary artery disease
• Left atrial enlargement
- Every 5 mm increase in left atrium diameter increases the risk
of AF by 39%
8
Pathophysiology and thromboembolic
risk of valvular heart disease
9
Valvular heart disease
• Regurgitation:
- ‘leaky’ valves that
cause backflow of
blood
• Stenosis:
- narrowing of valve
opening that causes
restricted blood flow
10
Mitral stenosis
Laupacts A et al. Chest. 1995:108:352S-9S.
Diker E et al. Am J Card 1996:77(1):96-8.
Mitral valve stenosis. Available at: mayoclinic.org
• Incidence:
- 29% of those with mitral
stenosis have AF
• Thromboembolic risk:
- Low blood flow increases risk
of thrombi due to stasis
- 15x more likely to have a
stroke in mitral stenosis with
AF
Mitral Valve Repair Bioprosthetic Valve Mechanical Valve
Factors to
consider• Native valve remains
• Used to treat mitral
regurgitation
• Last 10-20 years
• Do not require lifelong
anticoagulation
• Longest lasting type of
valve replacement
• Require life long
anticoagulation
Thrombo-
embolic
(TE) Risk
• Small risk of TE with
the highest risk
occurring during the
first year after
surgery
• Annual TE rates up to
0.7% with no
anticoagulation
• Highest risk of TE first
year after surgery
• Annual TE rates up to
4% with no
anticoagulation
• Mitral valves are 2x
higher risk of TE than
aortic valves
11
Valve repair and replacement
Cannegieter S et al. 1994;89:635-41.
Williams JB et al. Ann Thorac Surg 1980;30:247-58.
Iung B et al. Eur Heart J 2003;24:1231;1243.
Heras, M et al. J Am Coll Cardiol 1995;24:1111-9.12
Mechanism of mechanical valve thrombus
Hemodynamics• Slow blood flow
• Local blood flow turbulences
• Incomplete apposition
Hemostatics• Tissue injury
• Prosthesis malpositioning
Surface factors• Incomplete endothelialization
• Malpositioning
• Leaflet injury
Dangas G et al. J Am Coll Cardiol 2016;28:2670-89.
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13
Thromboembolic risk summary
Risk Stratum Valvular dysfunction
High • Mechanical heart valve
• Mitral stenosis
Low • Bioprosthetic valve
• Mitral valve repair
• Other native valve disease (mitral
regurgitation, etc)
Cannegieter S et al. 1994;89:635-41.
Williams JB et al. Ann Thorac Surg 1980;30:247-58.
Diker E et al. Am J Card 1996:77(1):96-8.
14
Defining valvular atrial fibrillation
• Non valvular atrial fibrillation (NVAF)
• CHA2DS2VASc score determines if anticoagulation is
necessary
• Valvular atrial fibrillation
• No clinical tool to evaluate anticoagulation modalities
• Bleeding risk assessment
• HAS-BLED
15
AF classifications and clinical tools
Molteni M, et al. Europace. 2014:16:1720-5.
Kirchhof P et al. Europace 2014:16:6-14.
Guideline Definition Anticoagulation Recommendations
AHA/ACC/HRS
2014 Atrial
Fibrillation
Guidelines
Rheumatic mitral
stenosis, mechanical or
bioprosthetic heart valve,
or mitral valve repair
• Mitral stenosis: VKA
• Mechanical valve: VKA
• Bioprosthetic valve: “DOAC use has
not been studied”
ESC/EACTS
2016 Atrial
Fibrillation
Guidelines
Moderate to severe
mitral stenosis or
mechanical heart valves
• Mitral stenosis: VKA
• Mechanical valve: VKA
• Bioprosthetic valve: “gap in
evidence”
European Heart
Rhythm
Association
2018 DOAC use
in AF Guidelines
Mechanical prosthetic
valves or moderate to
severe mitral stenosis.
Biological valves or valve
repair are in a ‘grey
area’.
• Moderate to severe mitral stenosis:
VKA
• Mechanical valve: VKA
• Bioprosthetic valve: DOACS
appropriate (except for 1st 3 months
post-op)
• Native valvular disease: DOACs
appropriate
Valvular AF guideline recommendations VKA = warfarin
Kirchhof P et al. Euro Heart Journ 2016;37: 2893-2962.
January C et al. J Americ Col Cardiol 2014;64:1-72.
Steffel J et al. Euro Heart Jounr 2018;39:1330-1393.
16
Guideline Definition Anticoagulation Recommendations
AHA/ACC/HRS
2014 AF
Guidelines
Rheumatic mitral
stenosis, mechanical or
bioprosthetic heart valve,
or mitral valve repair
• Mitral stenosis: VKA
• Mechanical valve: VKA
• Bioprosthetic valve: “DOAC use has
not been studied”
ESC/EACTS
2016 AF
Guidelines
Moderate to severe
mitral stenosis or
mechanical heart
valves
• Mitral stenosis: VKA
• Mechanical valve: VKA
• Bioprosthetic valve: “gap in
evidence”
European Heart
Rhythm
Association
2018 DOAC use
in AF Guidelines
Mechanical prosthetic
valves or moderate to
severe mitral stenosis.
Biological valves or valve
repair are in a ‘grey
area’.
• Moderate to severe mitral
stenosis: VKA
• Mechanical valve: VKA
• Bioprosthetic valve: DOACS
appropriate (except for 1st 3 months
post-op)
• Native valvular disease: DOACs
appropriate
Valvular AF guideline recommendations VKA = warfarin
Kirchhof P et al. Euro Heart Journ 2016;37: 2893-2962.
January C et al. J Americ Col Cardiol 2014;64:1-72.
Steffel J et al. Euro Heart Jounr 2018;39:1330-1393.
17
• Lack of internal homogeneity in valvular atrial fibrillation
- Pathogenesis of thromboembolism
- Thromboembolic risk
- Treatment needs
18
Why valvular atrial fibrillation is a misnomer
De Caterina R, et al. Eur Heart Journ. 2014:35:3328-35.
9/7/2018
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19
Thromboembolic risk summary
Risk Stratum Valvular dysfunction
High • Mechanical heart valve
• Mitral stenosis
Low • Bioprosthetic valve
• Mitral valve repair
• Other native valve disease (mitral
regurgitation, etc)
Cannegieter S et al. 1994;89:635-41.
Williams JB et al. Ann Thorac Surg 1980;30:247-58.
Diker E et al. Am J Card 1996:77(1):96-8.
Mechanical and rheumatic mitral valve atrial fibrillation
(MARM-AF)
20
DOAC trials in valvular atrial fibrillation
• FDA Indication:
non-valvular atrial
fibrillation
• Factor Xa Inhibition:
rivaroxaban, edoxaban,
apixaban
• Direct Thrombin Inhibitor:
dabigatran
21
DOAC review
Anticoagulation therapy: new opportunities, new challenges. Available at:
cardiologyreport.com22
DOAC use in valvular atrial fibrillation
Rivaroxaban Apixaban Edoxaban Dabigatran
Mitral stenosis
Mechanical
valves
Bioprosthetic
valves
Mitral valve
repairs/native
valve
dysfunction
• Study:- Multicenter, double blind, double dummy event driven trial
• Population- Significant valvular disease (SVD), n = 1,992
• Mitral valve repair, native valve disease (other than mitral stenosis)
- No significant valvular disease, n = 12,179
• Primary endpoints: - Efficacy: Composite of stroke and systemic embolism
- Safety: Major or non major clinically relevant bleeding or intracranial hemorrhage
23
ROCKET-AF
Breithardt G et al. Eur Heart Journ 2014;35:3377-85. 24
Efficacy outcomes as a function of the absence or
presence of significant valvular disease
Breithardt G et al. Eur Heart Journ 2014;35:3377-85.
SVD events/100
patient years
(total events)
No SVD events/100
patient years (total
events)
HR (95% CI)
SVD vs. no SVD
P-value
n = 1992 n = 12179
Stroke or SE 2.23 (88) 2.09 (487) 1.07 (0.85-1.35) 0.58
Stroke 1.92 (76) 1.96 (458) 0.98 (0.77-1.26) 0.89
Systemic embolism 0.32 (13) 0.14 (34) 2.02 (1.00-4.08) 0.049
All cause death 5.54 (212) 4.39 (1002) 1.09 (0.93-1.26) 0.29
SE = systemic embolism
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25
Safety outcomes as a function of the absence or presence
of significant valvular disease
Breithardt G et al. Eur Heart Journ 2014;35:3377-85.
SVD events/100
patient years
(total events)
No SVD
events/100 patient
years (total
events)
HR (95% CI)
SVD vs. no SVD
P-value
n = 1999 n = 12179
Major or NMCR
bleeding
18.24 (493) 14.16 (2431) 1.14 (1.03-1.25) 0.011
Major bleeding 5.11 (156) 3.27 (625) 1.32 (1.10-1.57) 0.0027
Intracranial
hemorrhage
0.80 (25) 0.59 (114) 1.35 (0.87-2.09) 0.18
NMCR = non-major clinically relevant
26
Efficacy of rivaroxaban vs warfarin in patients with and
without significant valvular disease
Breithardt G et al. Eur Heart Journ 2014;35:3377-85.
SVD, n = 1992 No SVD, n =12179
Rivaroxaban
events/100 pt
years
(total events)
Warfarin
events/100 pt
years
(total events)
Rivaroxaban
vs. warfarin
HR (95% CI)
Rivaroxaban
events/100 pt
years (total
events)
Warfarin
events/100 pt
years
(total events)
Rivaroxaban
vs. warfarin HR
(95% CI)
P-value for
interaction
of SVD and
treatment
Stroke
or SE
2.01 (38) 2.43 (50) 0.83
(0.55-1.27)
1.96 (231) 2.22 (256) 0.89
(0.75-1.07)
0.76
All
cause
death
5.48 (100) 5.60 (112) 0.98
(0.75-1.29)
4.19 (482) 4.60 (520) 0.91
(0.80-1.03)
0.60
27
Safety of rivaroxaban vs warfarin in patients with and
without significant valvular disease
Breithardt G et al. Eur Heart Journ 2014;35:3377-85.
SVD, n = 1999 No SVD, n =12179
Rivaroxaban
events/100 pt
years
(total events)
Warfarin
events/100 pt
years
(total events)
Rivaroxaban
vs. warfarin
HR (95% CI)
Rivaroxaban
events/100 pt
years (total
events)
Warfarin
events/100 pt
years
(total events)
Rivaroxaban
vs. warfarin
HR (95% CI)
P-value for
interaction
of SVD
and
treatment
Major or
NMCR
bleeding
19.81 (253) 16.83 (240) 1.25
(1.05-1.49)
14.19 (1222) 14.14 (1209) 1.01
(0.94-1.10)
0.034
Major
bleeding 6.14 (88) 4.20 (68) 1.56
(1.14-2.14)
3.22 (307) 3.33 (318) 0.98
(0.84-1.15)
0.010
Intracranial
hemorrhage 0.88 (13) 0.73 (12) 1.27
(0.58-2.79)
0.43 (42) 0.74 (72) 0.59
(0.40-0.86)
0.084
• No significant difference in rates of stroke and systemic
embolism in warfarin or rivaroxaban group in either SVD
or no SVD
• Higher bleeding rates seen in rivaroxaban use in
significant valvular heart disease than warfarin
• Rivaroxaban can be used in native valve disease with the
exception of mitral stenosis
28
Clinical application
29
DOAC use in valvular atrial fibrillation
Rivaroxaban Apixaban Edoxaban Dabigatran
Mitral stenosis No data
Mechanical
valves
No data
Bioprosthetic
valves
No data
Mitral valve
repairs/native
valve
dysfunction
• Study:
- Multicenter, randomized, double blind, double dummy trial
• Population:
- Valvular heart disease (VHD), n = 4,808
• Native valve diseases, bioprosthetic valves
- No valvular heart disease, n = 13,389
• Primary endpoints
- Efficacy: Rates of stroke or systemic embolism
- Safety: Major bleeding
30
ARISTOTLE
Avezum A et al. Circulation AHA 2015;1-13.
9/7/2018
6
31
Efficacy of apixaban vs warfarin in patients with and
without significant valvular disease
VHD, n = 4808 No VHD, n = 13389
Apixaban
events/100
pt years
(total
events)
Warfarin
events/100
pt years
(total
events)
Apixaban vs.
warfarin HR
(95% CI)
Apixaban
events/100
pt years
(total
events)
Warfarin
events/100
pt years
(total
events)
Apixaban vs.
warfarin HR
(95% CI)
P-
value
Stroke or SE 1.46 (64) 2.08 (89) 0.70 (0.51-0.97) 1.20 (148) 1.43 (176) 0.84 (0.67-1.04) 0.378
Stroke 1.37 (60) 2.03 (87) 0.67 (0.48-0.94) 1.12 (139) 1.33 (163) 0.85 (0.68-1.06) 0.257
Death from
any cause4.95 (222) 4.88 (215) 1.01 (0.84-1.22) 3.02 (381) 3.61 (454) 0.84 (0.73-0.96) 0.101
Breithardt G et al. Eur Heart Journ 2014;35:3377-85. 32
Safety of apixaban vs warfarin in patients with and without
significant valvular disease
VHD, n = 4788 No VHD, n =13350
Apixaban
events/100 pt
years
(total events)
Warfarin
events/100 pt
years
(total events)
Apixaban vs.
warfarin HR
(95% CI)
Apixaban
events/100 pt
years
(total events)
Warfarin
events/100 pt
years
(total events)
Apixaban vs.
warfarin HR
(95% CI)
P-value
Major
bleeding2.49 (99) 3.14 (119) 0.79 (0.61-1.04) 2.01 (228) 3.07 (343) 0.65 (0.55-0.77) 0.228
Intracranial
bleeding0.25 (10) 0.88 (34) 0.28 (0.14-0.57) 0.37 (42) 0.78 (88) 0.47 (0.33-0.68) 0.201
Major or
CRNM
bleeding
4.90 (191) 6.36 (235) 0.77 (0.64-0.93) 3.78 (422) 5.89 (642) 0.64 (0.57-0.73) 0.121
Breithardt G et al. Eur Heart Journ 2014;35:3377-85.
33
Aortic vs mitral valve heart disease
Breithardt G et al. Eur Heart Journ 2014;35:3377-85..
Apixaban rate %/year
(no. of events)
Warfarin rate %/year
(no. of events)
Hazard Ratio
(95% CI)
Mitral VHD n = 1801 n = 1777
Stroke or SE 1.32 (43) 1.89 (61) 0.70 (0.47-1.04)
Major bleeding 2.12 (63) 2.94 (84) 0.72 (0.52-1.00)
Aortic VHD n = 604 n = 546
Stroke or SE 1.57 (17) 2.88 (27) 0.55 (0.30-1.01)
Major bleeding 2.98 (29) 4.21 (34) 0.72 (0.44-1.18)
34
Bioprosthetic valve subgroup analysis
Pokorney SD et al. Circulation 2015;132;abstract 17277.
Apixaban number
(rates per 100
patient years)
Warfarin number
(rates per 100 patient
years)
P -value
n = 41 n = 41
Stroke or SE 2 (2.9) 0 (0) -
Major bleeding 4 (7.9) 3 (5.2) 0.61
All cause death 5 (6.9) 5 (7.1) 0.88
Cardiovascular
death
1 (1.4) 2 (2.8) 0.51
• Similar benefits of apixaban over warfarin were seen in
patients with and without valvular heart disease
• Apixaban is appropriate to use in native valvular disease
(excluding mitral stenosis) and bioprosthetic valves
35
Clinical application
36
DOAC use in valvular atrial fibrillation
Rivaroxaban Apixaban Edoxaban Dabigatran
Mitral stenosis No data No data
Mechanical
valves
No data No data
Bioprosthetic
valves
No data
Mitral valve
repairs/native
valve
dysfunction
9/7/2018
7
• Study:- Randomized, double blind, double dummy trial
• Population:- Bioprosthetic valves, n = 191
- Native valves, n = 20,914
• Primary endpoints:- Efficacy: Stroke or systemic embolic events
- Safety: Major bleeding
• Regimens:- LDER = low dose edoxaban regimen, 30 mg daily
- HDER = high dose edoxaban regimen, 60 mg daily
37
ENGAGE-AF
Carnicelli, A et al. Circulation 2017;135:1273-75. 38
Clinical outcomes in patients with bioprosthetic valves by
randomized treatment group
Carnicelli, A et al. Circulation 2017;135:1273-75.
• Edoxaban is appropriate to use in patients with atrial
fibrillation and bioprosthetic valves
39
Clinical application
Carnicelli, A et al. Circulation 2017;135:1273-75. 40
DOAC use in valvular atrial fibrillation
Rivaroxaban Apixaban Edoxaban Dabigatran
Mitral stenosis No data No data No data
Mechanical
valves
No data No data No data
Bioprosthetic
valves
No data
Mitral valve
repairs/native
valve
dysfunction
• Study:- Prospective, randomized, phase 2 open label trial with blinded end point
adjudication
• Population:- n = 252
- Population A: patients who had undergone mechanical aortic or mitral valve replacement within the past 7 days
- Population B: patients who had undergone mechanical aortic or mitral valve replacement at least 3 months earlier
• Outcomes:- Primary endpoint was the trough plasma concentration of dabigatran
- Additional efficacy and safety outcomes included stroke, systemic embolism, transient ischemic attack, valve thrombosis, bleeding, venous thromboembolism, myocardial infarction, and death
41
RE-ALIGN
Eikelboom, A et al. New Eng J Med 2013;369:1206-14. 42
Efficacy of dabigatran vs warfarin in mechanical heart
valves
Population A Population B
Dabigatran
(n=133), %
Warfarin
(n=66), %
Dabigatran
(n=35), %
Warfarin
(n=18), %
Hazard Ratio
(95% CI)
P-value
Death 1 3 0 0 0.25 (0.02-2.72) 0.2
Stroke 7 0 0 0 NA NA
Death,
stroke, TIA,
SE, or
myocardial
infarction
9 6 9 0 1.94 (0.64-5.86) 0.24
Eikelboom, A et al. New Eng J Med 2013;369:1206-14.
TIA = transient ischemic attack
9/7/2018
8
43
Safety of dabigatran vs warfarin in mechanical heart
valves
Eikelboom, A et al. New Eng J Med 2013;369:1206-14.
Population A Population B
Dabigatran
(n=133), %
Warfarin
(n=66), %
Dabigatran
(n=35), %
Warfarin
(n=18), %
Hazard Ratio
(95% CI)
P-value
Any
bleeding 26 12 29 11 2.45 (1.23-4.86) 0.01
Major
bleeding 5 3 0 0 1.76 (0.37-8.46) 0.48
Major
bleeding
with
pericardial
location
5 3 0 0 1.76 (0.36-8.45) 0.48
44
Clinical application
Eikelboom, A et al. New Eng J Med 2013;369:1206-14.
• Increased rates of thromboembolic and bleeding
complications when compared to warfarin
• Target dabigatran levels are unknown in this patient
population
• Dabigatran should not be used in patients with
mechanical heart valves
45
DOAC use in valvular atrial fibrillation
Rivaroxaban Apixaban Edoxaban Dabigatran
Mitral stenosis No data No data No data No data
Mechanical
valves
No data No data No data
Bioprosthetic
valves
No data No data
Mitral valve
repairs/native
valve
dysfunction
• Why were there such poor outcomes with dabigatran use
in mechanical heart valves?
46
Clinical Question
47 Action of anticoagulants in the coagulation cascade. Available at
radcliffecardiology.com
Eikelboom, A et al. New Eng J Med 2013;369:1206-14.
RR is a 67 year old male presenting to clinic with a new diagnosis of atrial fibrillation. Past medical history is significant for bioprosthetic mitral valve (placed 2013), hypertension, and gout. Patient also has a history of alcohol abuse and has a baseline INR of 1.3.
Which of the following anticoagulants is the most appropriate therapy for RR?
A. Warfarin
B. Enoxaparin
C. Apixaban
D. Rivaroxaban
48
Meet the patient…
9/7/2018
9
RR is a 67 year old male presenting to clinic with a new diagnosis of atrial fibrillation. Past medical history is significant for bioprosthetic mitral valve (placed 2013), hypertension, and gout. Patient also has a history of alcohol abuse and has a baseline INR of 1.3.
Which of the following anticoagulants is the most appropriate therapy for RR?
A. Warfarin
B. Enoxaparin
C. Apixaban
D. Rivaroxaban
49
Meet the patient…
• Rivaroxaban for VHD and AF trial
- Non-inferiority study of rivaroxaban vs warfarin in bioprosthetic mitral
valves for major clinical event outcomes
• Rivaroxaban vs warfarin in patients with metallic prosthesis
- Treatment study of rivaroxaban vs warfarin in mechanical heart valves
• Anti-thrombotic strategy after trans-aortic valve implantation
- Superiority study of apixaban vs standard of care (warfarin or dual
antiplatelet therapy) post TAVI in preventing cardiovascular events
• Investigation of rheumatic AF using VKA
- Superiority study of rivaroxaban vs aspirin in rheumatic heart disease
patients unable to take warfarin
50
What’s in the pipeline?
TAVI = trans aortic valve implantation
51
DOAC use in valvular atrial fibrillation
Rivaroxaban Apixaban Edoxaban Dabigatran
Mitral stenosis
Mechanical
valves
Bioprosthetic
valves
Mitral valve
repairs/native
valve
dysfunction
• The term valvular atrial fibrillation should be removed from
medical jargon
- MARM-AF is an appropriate alternative definition
• DOACs are appropriate to use in native valve disease
(excluding mitral stenosis) and in bioprosthetic valves
• DOAC use is inappropriate in mechanical heart valves
52
Conclusions
• Evaluator
- Bethany Kalich, PharmD, BCPS-AQ Cardiology
• Preceptors
- Evan Peterson, PharmD, BCPS
- Molly Curran, PharmD, BCPS, BCCCP
53
Acknowledgements
54
Questions?
9/7/2018
10
ASCENSION TEXAS
Nina Maguire, PharmD
September 14, 2018
DOAC Use in Atrial Fibrillation with Valvular
Heart Disease
Appendices
Appendix A: CHA2DS2VASc Score
Appendix B: CHA2DS2VASc Risk of Stroke
Appendix C: HAS-BLED Score
Appendix D: HAS-BLED Risk of Bleed
Appendix E: Abbreviations
Appendix A: CHA2DS2VASc Score
CHA2DS2VASc Risk Score
Congestive heart failure/left ventricular dysfunction
1
Hypertension 1
Aged ≥ 75 years 2
Diabetes mellitus 1
Stroke/Transient Ischemic Attack/Thromboembolism
2
Vascular disease (prior myocardial infarction, peripheral artery disease, or aortic plaque)
1
Aged 65-74 years 1
Sex category (female) 1
Lane, D et al. Circulation 2012;126:860-865.
Appendix B: CHA2DS2VASc Stroke Risk
Score CHA2DS2VASc Adjusted Stroke Rate (%/year)
0 0
1 1.3
2 2.2
3 3.2
4 4.0
5 6.7
6 9.8
7 9.6
8 6.7
9 15.2
Lane, D et al. Circulation 2012;126:860-865.
Appendix C: HAS-BLED Score
HAS-BLED risk Score
Hypertension (systolic blood pressure >160 mmHg)
1
Abnormal renal/liver function
1 point each
Stroke 1
Bleeding tendency or pre-disposition
1
Age > 65 years 1
Drugs (concomitant aspirin or NSAIDs) or alcohol
1 point each
Lane, D et al. Circulation 2012;126:860-865.
Appendix D: HAS-BLED Bleeding Risk
Score HAS-BLED Risk of Major Bleeding/Year (%)
0 1.1
1 1.0
2 1.9
3 3.7
4 8.7
5 12.5
>5 Undetermined
Lane, D et al. Circulation 2012;126:860-865.
Appendix E: Abbreviations
DOAC: direct oral anticoagulant
AF: atrial fibrillation
TE: thromboembolic
NVAF: non-valvular atrial fibrillation
VKA: warfarin
MARM-AF: mechanical and rheumatic mitral valve atrial fibrillation
SVD: significant valvular disease
SE: systemic embolism
NMCR: non-major clinically relevant
VHD: valvular heart disease
HDER: high dose edoxaban regimen
LDER: low dose edoxaban regimen
TIA: transient ischemic attack
TAVI: transcatheter aortic valve implantation