direct oral anticoagulant use in valvular atrial...

Direct Oral Anticoagulant Use in Valvular Atrial Fibrillation

September 14, 2018

Nina Maguire, PharmD

PGY1 Pharmacy Resident

Seton Healthcare Family

[email protected]

9/7/2018

1

ASCENSION TEXAS


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.

9/7/2018

3

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)




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



• 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


• 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



• Bioprosthetic valve: “DOAC use has

not been studied”

ESC/EACTS

2016 AF

Guidelines

Moderate to severe

mitral stenosis or

mechanical heart

valves



• 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


• 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

4

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)




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

9/7/2018

5

25

Safety outcomes as a function of the absence or presence

of significant valvular disease


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


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



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



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


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


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


36



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


Carnicelli, A et al. Circulation 2017;135:1273-75. 40



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


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



• 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



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




A. Warfarin

B. Enoxaparin

C. Apixaban

D. Rivaroxaban

48

Meet the patient…

9/7/2018

9



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



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


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


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


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


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

direct oral anticoagulant use in valvular atrial...

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