© 2017 MFMER | 3629471-1

NOAC for Structural Heart Disease: Update

Korean Heart Rhythm Society, SeoulPeter Noseworthy, MDAssociate ProfessorMayo Clinic

June 23rd , 2017

© 2017 MFMER | 3629471-2

81F admitted with TIA

Found to be in AF

History of HTN

Prior mitral valve repair with annuloplasty ring

On no OAC at time of TIAWhat would you recommend?

© 2017 MFMER | 3629471-3

Many considerations…..

Is this ‘valvular’ AF?

Can NOACs be considered?

Is OAC warranted?

© 2017 MFMER | 3629471-4

Timeline

1944

Warfarin discovered (Wisconsin Alumni Research Fund)

Dabigatran (2010)

Rivaroxaban (2011)

Apixaban (2012)

Edoxaban (2015)

FDA approval of 1st NOAC

Warfarin Era NOAC Era20101954

Warfarin approved for OAC

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Emergence of NOACs Post Ablation

Year of Ablation

Dagbigatran

Warfarin

Rivaroxaban

Apixaban

%

0

20

40

60

80

100

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Noseworthy JAHA 2015

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1. NEJM 2009

2. NEJM 2011

3. NEJM 2011

4. NEJM 2013

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Trial Data: Stroke or SE

Ruff Lancet, 2015

Dabigatran

Rivaroxaban

Apixaban

Edoxaban

Combined (random effects)

0.66 (0.53-0.82) 0.0001

0.88 (0.75-1.03) 0.12

0.80 (0.67-0.95) 0.012

0.88 (0.75-1.02) 0.10

0.81 (0.73-0.91) <0.0001

Favor NOAC Favor Warfarin

1.00.5 0.75

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Trial Data: Major Bleeding

Ruff Lancet, 2015

0.94 (0.82-1.07) 0.34

1.03 (0.90-1.18) 0.72

0.71 (0.61-0.81) <0.001

0.80 (0.71-0.90) 0.0002

0.86 (0.73-1.0) 0.06

Dabigatran

Rivaroxaban

Apixaban

Edoxaban

Combined (random effects)

Favor NOAC Favor Warfarin

1.00.5 0.75

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Trial Data: Intracranial Bleeding

Ruff Lancet, 2015

0.40 (0.27-0.60)

0.67 (0.47-0.93)

0.42 (0.30-0.58)

0.47 (0.41-0.55)

0.48 (0.39-0.59) <0.0001

1.00.5 0.75

Dabigatran

Rivaroxaban

Apixaban

Edoxaban

Combined

Favor NOAC Favor Warfarin

© 2017 MFMER | 3629471-10

What about structural heart disease?

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1. Valvular heart

disease

2. Hypertrophic

cardiomyopathy

3. Congenital heart

disease

Subgroup analyses from RCTs,

meta-analyses, observational data

Observational data

Expert opinion, observational data

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“Valvular” AF in the Guidelines

Rheumatic MS

Non-rheumatic MS

Mechanical valves

Tissuevalves

Valve repair

Other native valve

disease

2006/2011 ACC/AHA/HRS guideline + update

X X X X

2012

ESC updateX X

2014

AHA/ACC/HRSX X X X

2015 EHRA guideline

XX

(if moderate to severe)

X

2017 AHA/ACCupdate

X X X

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Without AF…..AHA/ACC VHD Guidelines (Update 2017)

Mechanical Bioprosthetic TAVR MV Repair

VKA Goal INR:

• 3 for mitral and

Ao with risk

factors (I)

• 2.5 for Ao (I)

• 1.75 for On-

X** (IIb)

INR 2.5 for 3-6

months if mitral

(IIa)**

INR 2.5 for 3

months (IIb)

INR 2.5 for first

3 months (IIa)

NOAC CLASS III ? ? ?

Antiplatelet In addition to

VKA if no

contraindication

(I)

Indefinite ASA

(IIa)

Clopidogrel +

ASA for 6

months, ASA

indefinitely (IIb)

Nishimura Circ 2014**Nishimura Circ 2017

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RE-ALIGN Trial: Dabigatran vs. Warfarin

Phase 2 dose-validation study

Two populations:AVR/MVR within the past 7 days

AVR/MVR 3 months earlier

Randomized 2:1 to dabigatran or warfarin

n=252

Eikelboom NEJM, 2013

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RE-ALIGN Trial: Dabigatran vs. Warfarin

0.0

0.2

0.4

0.6

0.8

1.0

0 50 100 150 200 250 300 350 400

Eikelboom NEJM, 2013

Pro

babili

ty o

f N

o E

vent

DaysNo. at risk

Dabigatran 168 156 126 108 73 44 15 7

Warfarin 84 82 66 55 40 22 9 4

Warfarin

Dabigatran

First Thrombeombolic Event

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End of this line of investigation…

No data available for apixaban, rivaroxaban, or edoxaban

Is the risk real (only ~250 pts)?

Is the risk specific to direct thrombin inhibitors?

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Preclinical Work: APIXABAN

CONTROL APIXABAN WARFARIN

Valv

e thom

bus

weig

ht

(mg)

Lester Arterioscler Thromb Vasc Biol., 2017

1,422

338

676

357.5

105234.9247.1

77.5 134.3

0

500

1,000

1,500

Mean SEM SD

Control 30 d Apixaban Oral 30 d* Warfarin Oral 30 d*

P=4

P=5

P=3

Valve Thrombus Weight (mg) in Swine

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Will Apixaban have a role in mechanical valves one day?

“Data from such studies may provide the foundation for future clinical studies evaluating apixaban as an alternative to warfarin in select

patients with mechanical heart valves.”

Lester Arterioscler Thromb Vasc Biol. 2017

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What about other forms of valvular heart disease?

What do the trials tell us?

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Rheumatic

MS

Non-

rheumatic MS

Mechanical

valves

Tissue

valves Valve repair

Other native

valve disease

RE-LY X193 pts

(mild-mod) *X X X

n=3,950* (21.8%)

3,101 MR

817 AR

471 AS

ROCKET-AF X X X X

106 pts

(valvuloplasty or

other procedure)

N=2003 (14.1%)

1,756 MR

486 AR

215 AS

ARISTOTLEX

(if HS)

69 pts

(mild-mod)X 119 pts 132 pts

N=2438 (26.4%)

1,778 MR

462AR

208 AS

ENGAGE-AFX X X

191

(131 mitral

60 aortic)Included N=2,824

NOAC-Treated “Valvular AF” in Trials

X = excludedHS = hemodynamically significant

* Includes VKA-treated pts

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Valvular Disease: Stroke or SE

Siontis, Noseworthy Circ 2017

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Valvular Disease: Major Bleeding

Siontis, Noseworthy Circ, 2017

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Meta-Analysis by Another Group

Renda, JACC 2017

© 2017 MFMER | 3629471-24

Rheumatic

MS

Non-

rheumatic MS

Mechanical

valves

Tissue

valves Valve repair

Other native

valve disease

RE-LY X193 pts

(mild-mod) *X X X

n=3,950* (21.8%)

3,101 MR

817 AR

471 AS

ROCKET-AF X X X X

106 pts

(valvuloplasty or

other procedure)

N=2003 (14.1%)

1,756 MR

486 AR

215 AS

ARISTOTLEX

(if HS)

69 pts

(mild-mod)X 119 pts 132 pts

N=2438 (26.4%)

1,778 MR

462AR

208 AS

ENGAGE-AFX X X

191

(131 mitral

60 aortic)Included N=2,824

NOAC-Treated “Valvular AF” in Trials

X = excludedHS = hemodynamically significant

* Includes VKA-treated pts

© 2017 MFMER | 3629471-25

ENGAGE-AF: Bioprosthetic ValvesMajor Bleeding

0

2

4

6

8

10

12

14

16

18

20

0.0 0.5 1.0 1.5 2.0 2.5 3.0

Carnicelli Circulation, 2017

Majo

r ble

edin

g

Years

Warfarin (n=69) 69 61 53 47 43 30 14

High dose E (n=63) 63 52 47 41 39 23 11

Low dose E (n=58) 58 51 47 44 40 32 19

Warfarin

HDER (n=63)

LDER (n=58)

High dose edoxaban vs Warfarin: HR 0.50 (95% CI 0.15-1.67); P=0.26

Low dose edoxaban vs Warfarin: HR 0.12 (95% CI 0.01-0.95); P=0.045

© 2017 MFMER | 3629471-26

ENGAGE-AF: Bioprosthetic ValvesPrimary Net Clinical Outcome

02468

1012141618202224262830

0.0 0.5 1.0 1.5 2.0 2.5 3.0

Carnicelli Circulation, 2017

Net

clin

ical outc

om

e

Years

Warfarin (n=70) 70 62 52 45 41 28 13

High dose E (n=63) 63 52 45 41 39 23 11

Low dose E (n=58) 58 51 47 44 40 32 19

Warfarin

HDER (n=63)

LDER (n=58)

High dose edoxaban vs Warfarin: HR 0.46 (95% CI 0.23-0.91); P=0.03

Low dose edoxaban vs Warfarin: HR 0.43 (95% CI 0.21-0.88); P=0.02

© 2017 MFMER | 3629471-27

ARISTOTLE: Bioprosthetic Valves (abstract)

Interim report on 82 of 260 patients with a history of valve surgery from ARISTOTLE (data collection ongoing)

41 patients each were in the apixaban and warfarin arms

Pokorney AHA scientific sessions, 2016

© 2017 MFMER | 3629471-28

ARISTOTLE: Bioprosthetic Valves (abstract)

Apixaban

(n=41)

Warfarin

(n=41)

P

Event Number (rate*) Number (rate*)

Major bleeding 4 (7.9) 3 (5.2) 0.61

Stroke/Systemic embolism 2 (2.9) 0 (0) –

All-cause death 5 (6.9) 5 (7.1) 0.88

Cardiovascular death 1 (1.4) 2 (2.8) 0.51

*Rates per 100 patients-years of follow-up

Pokorney AHA scientific sessions, 2016

No clear signal of risk…..more data

and follow up needed

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What about TAVR?

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TAVR: Subacute Valve Thrombosis is Rare But Clinically Important

26/4,266 patients (0.61%) post TAVR at 12 centers

• 20 Edwards Sapien/Sapien XT

• 6 Medtronic CoreValve cohort

TTE Gross Path

Cusp

Latib Circ Cardiovasc Interv, 2016

© 2017 MFMER | 3629471-31

Apixaban: Post TAVR

**Recall: current guidelines recommend VKA x3 months,

then antiplatelet therapy indefinitelySeeger JACC Interv, 2017

Pre-procedure

48 hrs

30 days

12 months

Stop VKA 7 days/non-VKA 2 days prior to TAVR

Continuous aspirin 100 mg/d orLoading dose 500 mg

Transfemoral TAVRn=617

Atrial fibrillation/new-onset AFn=272

Antiplatelet therapy for 4 weeks

Restart oral anticoagulation 48 hrs post TAVR

Sinus rhythmn=345

VKAn=131

Apixabann=141

30 days follow-up

12 months follow-up

Antiplatelet therapy

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Apixaban: Post TAVR

Days

Short-Term Outcomes Long-Term Outcomes (Stroke)

Seeger JACC Interv, 2017

100

95

90

85

0

%

0 50 100 150 200 250 300 350

1.4

0.7

2.12.3

1.5

3.8

0

1

2

3

4

5

All-causemortality

disabling andnon-disabling

stroke

Secondaryoutcomemeasure

Apixaban Vitamin k antagonist

P=0.60

P=0.52

P=0.42

(n=2/141) (n=3/141) (n=1/141) (n=2/131) (n=3/141) (n=5/131)

%

© 2017 MFMER | 3629471-33

What can we learn from large observational datasets?

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>110 millionAdministrative

Data source: Optum Labs Data Warehouse

2,000+ fields:• Medical claims

• Pharmacy claims

• Lab claims and results

• Health risk assessments

• Standardized costs of care

• Race

• Income

• Education level

• Language preference

• Household

• Geography

• Mortality

315 million U.S. population

>30 million

Clinical

500+ additional EHR fields:• Encounters

• Vitals

• Labs

• Medication orders

• Procedures

• Admissions, discharges, transfers

• Patient appointments

• PHQ-9

• Patient-provided information

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• Age

• Gender

• Race

• Income

• Region

• Charlson-Deyo

• CHA2DS2-VASc

• HAS-BLED

• Individual score

components

• Previous warfarin

exposure

Cohort Creation

Inclusion:

10/1/2010 and 4/30/2015

AF + valvular heart disease

Apixaban, dabigatran,

rivaroxaban or warfarin use

+12 month continuous

enrollment

Exclusion:

Dialysis, kidney transplant

N=164,612

(N=20,158 NOAC)

PS-matched cohorts

3:1 warfarin:NOACs

Post-surgical

• Bioprosthetic valves

• Valve repairs

Native

• Rheumatic MS

• Non-rheumatic MS

• AS/AI or MR

PS

match

© 2017 MFMER | 3629471-38

Native valves: NOAC vs Warfarin

Stroke or systemic

embolismMajor bleeding

N on NOAC HR (95% CI) p HR (95% CI) p

AS/AI or MR 19,351 0.76 (0.59, 0.98) 0.03 0.84 (0.72, 0.97) 0.02

Non-rheumatic MS 654 0.51 (0.15, 1.77) 0.29 0.84 (0.44, 1.61) 0.60

Rheumatic MS 74 NA 0.35 (0.04, 3.33) 0.36

Noseworthy, Yao IJC, 2016

© 2017 MFMER | 3629471-39

Surgical Valves: NOAC vs Warfarin

Stroke or systemic

embolismMajor bleeding

N on NOAC HR (95% CI) P HR (95% CI) P

Bioprosthetic valves 24 NA NA

Valve repairs 55 NA 0.77 (0.08, 7.84) 0.82

Noseworthy, Yao IJC, 2016

© 2017 MFMER | 3629471-40

Which Patients Cannot Get NOACs?

Data support a more restrictive definition consistent with ESC and EHRS guidelinesRheumatic mitral stenosis, mechanical heart valves

NOAC may be preferable for MR, AS, and reasonable for valve repair or replacement not independently requiring anticoagulation

© 2017 MFMER | 3629471-41

1. Valvular heart

disease

2. Hypertrophic

cardiomyopathy

3. Congenital heart

disease

Subgroup analyses from RCTs,

meta-analyses, observational data

Observational data

Expert opinion, observational data

© 2017 MFMER | 3629471-42

Hypertrophic cardiomyopathy

What about NOAC?1 in 5 risk of AF

4% annual stroke risk

Anticoagulation is indicated

Associated with functional valvular disease

US and European guidelines consider NOAC an option in HCM, but note that no data are available

© 2017 MFMER | 3629471-45

HCM: Effectiveness outcomes

NOAC vs Warfarin

Stroke or SE 1.93 2.03 0.92 (0.32, 2.63)

Ischemic stroke 1.61 1.12 1.37 (0.40, 4.67)

Hemorrhagic stroke 0.32 0.91 0.35 (0.04, 3.36)

Favor NOAC

Event rate per 100 person-years Hazard ratio (95% CI)

Favor Warfarin

1.0 1.5 2.00.50.0 2.5 3.0

Noseworthy, Yao JACC, 2016

© 2017 MFMER | 3629471-46

HCM: Safety outcomes

NOAC vs Warfarin

Major bleeding 4.18 5.38 0.75 (0.36, 1.57)

Intracranial bleeding 0.32 1.12 0.26 (0.03, 2.25)

GI bleeding 3.22 4.06 0.77 (0.33, 1.82)

Favor NOAC

Event rate per 100 person-years Hazard ratio (95% CI)

Favor Warfarin

1.0 1.5 2.00.50.0 2.5 3.0

Noseworthy, Yao JACC, 2016

© 2017 MFMER | 3629471-47

HCM: S/SE Stratified by Baseline Risk

NOAC vs Warfarin

Overall 1.93 2.03 0.92 (0.32, 2.63)

CHA2DS2-VASc 0, 1 2.01 1.25 1.70 (0.11, 27.31)

CHA2DS2-VASc 2, 3 0.91 2.77 0.31 (0.03, 2.79)

CHA2DS2-VASc ≥4 2.64 1.80 1.44 (0.34, 5.82)

1.0 1.5 2.00.50.0 2.5 3.0

Event rate per 100 person-years Hazard ratio (95% CI)

Favor NOAC Favor Warfarin

Noseworthy, Yao JACC, 2016

© 2017 MFMER | 3629471-48

1. Valvular heart

disease

2. Hypertrophic

cardiomyopathy

3. Congenital heart

disease

Subgroup analyses from RCTs, meta-

analyses, observational data

Observational data

Expert opinion, observational data

© 2017 MFMER | 3629471-49

Early Clinical Experience

Single center (Munich, DE) Abstract

n=102,

2 months follow-up

No strokes reported, one bleeding event

Pujol AJC, 2015

Congenital Heart Disease n (%)

Hypoplastic left heartDouble inlet left ventricleDouble outlet right ventricle (univentricular repair)Transposition of great arteriesCongenital corrected transposition of great arteriesAortic coarctationAortic stenosisSubaortic stensisAortic regurgitationTetralogy of FallotDouble outlet right ventricle/Fallot-typePulmonary atresia with ventricular septal defectVentricular septal defectPatent ductus arterioususPatent foramen ovaleAtrial septal defectEbstein’s anomalyAneurysm of AortaEctasia great arteriesOthers

2 (3%)2 (3%)1 (1%)

10 (13%)1 (1%)1 (1%02 (3%)1 (1%)1 (1%)5 (7%)2 (3%)2 (3%)2 (3%)1 (1%)9 (12%)22 (29%)6 (8%)1 (1%)2 (3%)2 (3%)

© 2017 MFMER | 3629471-50

Ongoing Registry: NOTE Registry

Multicenter prospective registry Adult CHD patients with atrial tachyarrhythmias

All on NOACs (switch from VKA or new on anticoagulants)

2 years of follow up

April 2014-2018

Goal 300 patients

University of Amsterdam (Dr. Mulder)

© 2017 MFMER | 3629471-51

2014 Guideline Algorithm: Approach To OAC

Long-term thromboprophylaxis

NoYes

VKA

Moderate/complex CHD

Simple CHD

Prosthetic valve orsignificant valve disease?

0

No thromboprophylaxis No thromboprophylaxis or ASA VKA or NOAC

CHA2DS2-VASc score

Khairy JACC, 2015

1 2

© 2017 MFMER | 3629471-52

81F admitted with TIA

Found to be in AF

History of HTN

Prior mitral valve repair with annuloplasty ring

On no OAC at time of TIAWhat would you recommend?

© 2017 MFMER | 3629471-53

Question: What would you recommend?

1. No anti-thrombotic therapy

2. ASA 81mg alone

3. Warfarin

4. NOAC

5. Combination ASA/clopidogrel