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ACOFP / AOA’s 122nd Annual Osteopathic Medical Conference & Exposition

OCTOBER 7 - 10PHILADELPHIA, PENNSYLVANIA29.5 Category 1-A CME credits anticipated

OMED 17®

ACOFP - The Heart of the Matter - An Evidence Based Approach to Common Cardiovascular Concerns:

Atrial Fibrillation - Keeping Your Patients Safe

Bruce Kornberg, DO

10/8/2017

1

Outline

• Introduction: Stroke and atrial fibrillation (AF)

• Assessing stroke risk in patients with AF

• Safety, efficacy, and selection of appropriate antithrombotic therapy– Clinical case

– Clinical guidelines

• Emerging antithrombotic therapies– Potential clinical application

• Concluding remarks/Q&A

10/8/2017

2

Atrial Fibrillation (AF)• Estimated to affect 2.7 to 6.1 million patients in US

• Most common arrhythmia requiring hospitalization

– More than 750,000 yearly secondary to AF

• Associated with advanced age and chronic heart disease—especially heart failure—as well as high blood pressure, obesity, diabetes, and hyperthyroidism

• Independent risk factor for stroke

• Increases stroke risk by four to five times compared to those without AF

• Underdetected

Fuster V, et al. Circulation. 2006;114:700-752.; Thom T, et al. Circulation. 2006;113:e85-e151.; Mozaffarian D. Benjamin EJ, Go AS,

Arnett DK, Blaha MJ, Cushman, M, et al. Heart Disease and Stroke Statistics-2015 update: a report from the American Heart

Association, Circulation. 2015;131:e29-e322

Persistent(Not self-terminating)

Paroxysmal(Self-terminating)

First Detected

Permanent

Classification of AFACC/AHA/ESC Guidelines

Fuster V, et al. J Am Coll Cardiol. 2006;48:e149-e246.

10/8/2017

3

Furberg CD, et al. Am J Cardiol .1994;74:236-241.

Blackshear JL, et al. Lancet. 1996;348(9028):633-638.

Sparks PB, et al. Pacing Clin Electrophysiol.1998;21:1258-1267.

AF Underdetection

• Cardiovascular Health Study: 30% unaware of AF documented by ECG

• SPAF III: 44% of AF detected by ECG without AF symptoms

• Sparks et al: 48/110 pacemaker patients noted to be in AF during routine interrogation; most were high risk for stroke

• AF is responsible for 15% to 20% of

ischemic strokes

– AF increases one’s risk of suffering an

ischemic stroke fivefold

• AF is responsible for ~30% of strokes

in patients >80 years old

– Pathogenesis: Caused by atrial

thrombosis and thromboembolism

(principally from the left atrial appendage)

AF and Stroke

10/8/2017

4

• AF-related strokes more severe; result in higher mortality

• Patients with AF are not always appropriately risk-stratified for stroke

• Appropriate anticoagulation for patients at risk is underutilized

• Poorly controlled anticoagulation is associated with elevated stroke risk

• Appropriate antithrombotic treatment requires weighing the risks and benefits of stroke prevention vs hemorrhagic complication

AF and Stroke

Wyse DG, et al. N Engl J Med. 2002;347(23):1825-1833.; Furberg CD. Am J Cardiol. 1994;74:236.; Blackshear JL, et al. Lancet.

1996;348(9028):633-638.; Sparks PB, et al. Pacing Clin Electrophysiol.1998;21:1258-1267.

Paroxysmal vs Chronic AF• Risk of stroke is the same

• Symptomatic vs asymptomatic: does not affect stroke risk assuming same level of treatment

• AFFIRM trial: rate vs rhythm control– Most strokes occurred with discontinuation of

anticoagulation after perception of rhythm control

– One ECG showing SR does not rule out possibility of recurrent AF

10/8/2017

5

Central Nervous System EventOverall (N

= 4060)

Rate

Control

Group

(N = 2027)

Rhythm

Control

Group (N

= 2033)

P

Value

Total 211 (8.2) 105 (7.4) 106 (8.9) .93

Ischemic stroke 157 (6.3) 77 (5.5) 80 (7.1) .79

After discontinuation of warfarin 69 25 44

During warfarin but with INR <2.0 44 27 17

Concurrent atrial fibrillation 67 42 25

Primary intracerebral hemorrhage 34 (1.2) 18 (1.1) 16 (1.3) .73

Subdural or subarachnoid hemorrhage 24 (0.8) 11 (0.8) 13 (0.8) .68

Thromboembolic ComplicationsAFFIRM

61% of strokes in “pseudo” Rhythm Control Group occurred after stopping or with inadequate warfarin;

documented asymptomatic AF in ~ 50%

Wyse DG, et al. N Engl J Med. 2002;347(23):1825-1833.

CHADS2VASc Risk Stratification

Scheme

Gage BF, et al. JAMA. 2001;285(22):2864-2870.

Congestive heart failure 1

Hypertension 1

Age > 75 2

Diabetes 1

Stroke/TIA/TE 2

Vascular disease (MI, PAD, aortic plaque) 1

Age 65-74 1

Female sex 1

CHA2DS2-VASc 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%

10/8/2017

6

Case StudyChoice of Therapy

• You estimate that your patient’s annual stroke

risk is around 6%-9%.

• What is her bleeding risk?

• What is her “best management” to reduce

long term stroke risk?– Discuss risks and benefits of antithrombotic

therapy with patient

– Determine patient preference & ability to safely

take anticoagulant

– Establish protocol for monitoring

What About Bleeding Risk? • Risk factors for anticoagulation-related bleeding

complications: – Advanced age– Uncontrolled hypertension– History of myocardial infarction or ischemic heart disease– Cerebrovascular disease– Anemia or a history of bleeding

– Concomitant use of other drugs such as antiplatelet agents

• Many risk factors for anticoagulation-related bleeding are also indications for the use of anticoagulants in AF patients, given the increasing bleeding risk with increasing CHADS2VAScscore

• Various bleeding risk stratification schema have been proposed, but more validation of their value is required in prospective cohorts of AF patients

10/8/2017

7

HAS-BLED

• Hypertension=1

• Abnormal renal/liver function=1

• Stroke=1

• Bleeding history or disposition=1

• Labile INR=1

• Elderly=1

• Drugs/Alcohol=1

ClinicallyRelevant Bleeding

Major Bleeding

0 7% 1%

1 8% 1%

2 11% 2%

3 16% 3%

4 15% 3%

>5 38% 8%

American College of Chest Physicians (ACCP) Guidelines Recommendations

CHADS2 Score Risk Factor Recommended Therapy

≥2 points Warfarin

(target INR 2.5, range 2.0-3.0)

1 point Aspirin 75 mg to 325 mg QD or

warfarin (target INR 2.5, range

2.0-3.0)

Age ≤75 years with no Aspirin 75 mg to 325 mg QD

risk factors

Singer DE, et al. Chest. 2008;133:546S–592S.

CHADS2 Score risk factors: (1) age >75 years; (2) history of hypertension; (3)

diabetes mellitus; and (4) moderately or severely impaired left ventricular

systolic function and/or heart failure

10/8/2017

8

Warfarin• Most commonly used oral anticoagulant

– >60 years of use– Well-studied

• Reduces vitamin K dependent clotting factors

• Very effective if INR kept in therapeutic range– Effect measured using the INR;

therapeutic range: 2-3

• Well-known and defined drug and food interactions

• Relatively inexpensive

Meta-Analysis of Warfarin Efficacy and Safety

• 15 large studies comparing warfarin to ASA or placebo in patients with atrial fibrillation

• Warfarin vs placebo = 71% RRR

• Warfarin vs ASA = 50% RRR

• Both statistically significant

• Warfarin vs placebo increased risk of major bleed by OR = 3.0

Andersen LV, et al. Heart. 2008;94(12):1607-1613.

10/8/2017

9

Efficacy of WarfarinStroke Risk Reductions

Andersen LV, et al. Heart. 2008;94(12):1607-1613.

Hart RG, et al. Ann Intern Med. 1999;131:492-501.

Warfarin Better Control Better

AFASAK

SPAF

BAATAF

CAFA

SPINAF

EAFT

100% 50% 0 -50% -100%

Reduction ofstroke

RRR 62%

Reduction ofall-cause mortality

RRR 26%

All trials = 6

Aspirin vs PlaceboStroke Risk Reductions

AFASAK I

SPAF I

EAFT

ESPS II

LASAF

UK-TIA

All trials = 6

Relative Risk Reduction (95% CI)

100 50 0 -50 -100Aspirin

22% (2%-38%)

Hart RG, et al. Ann Intern Med. 1999;131:492-501.

10/8/2017

10

Efficacy of Aspirin vs Warfarin

AFI. Arch Int Med. 1994;154:1449-1457.; van Walraven C, et al. JAMA. 2002; 288(19):2441-2448.

68%

21%

52%

0

20

40

60

80

100

Warfarin vs No

Therapy

ASA vs No

Therapy

Warfarin vs ASA

Rela

tive

Ris

k R

ed

uc

tio

n, %

ACTIVE-A: Asprin vs. Clopidogrel + Aspirin

Cumulative Risk of Stroke

Connolly SJ, et al. New Engl J Med. 2009;360:2066-2078.

3772 3488 3225 2567 11973782 3459 3155 2516 1184

No. at Risk

ASAC+A

Cum

ula

tive H

azard

Rate

s0

.00

.05

0.1

00

.15

0 1 2 3 4

Aspirin

Clopidogrel + aspirin

HR = 0.72 (0.62-0.84), P = .00002

Years

10/8/2017

11

*ACTIVE = Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events; Primary outcome: stroke, systemic embolus, MI, vascular death; Clopidogrel + aspirin = 5.6% risk/year vs warfarin = 3.93% risk/year.

Connolly S, et al. Lancet. 2006;367:1903-1912.

YearsNumber at risk

Clopidogrel 3335 3168 2419 941+ aspirin

Oral anti- 3371 3232 2466 930coagulation therapy

Clopidogrel + Aspirin vs Oral Anticoagulation

Active-W: Cumulative Risk of Stroke

0

RR = 1.72 (1.24-2.37), P = .001

Clopidogrel + aspirin

Oral anticoagulation therapy

0

0.01

0.02

0.05

0.04

0.03

Cum

ula

tive

Ha

za

rd R

ate

s

0.5 1 1.5

Rates of Intracranial Hemorrhage (ICH) With Anticoagulation in Patients With AF

• Precise estimates of anticoagulant-associated

ICH are not available

• Generally thought to be in 1%-2% per yr range

– Some studies as low as 0.4% per yr; some as high as

3%-4% per yr*

• Several risk factors– Age, HTN, prior strokes, leukoaraiosis, high INR,

cerebral amyloid angiopathy

*Includes heparin use

Flaherty ML, et al. Neurology. 2007;68(2):116-121.

10/8/2017

12

WarfarinTime in Range

• Meta-analysis of 8 studies

• 14 unique warfarin treated groups

• Mean, 95% confidence intervals for

time in range = 55% (51%-58%)

Baker WL, et al. J Manag Care Pharm. 2009;15:244-252.

Time in range correlates with freedom from stroke:

retrospective study of 6108 patients in the United Kingdom

Morgan CL, et al. Thromb Res. 2009;124(1):37-41.

WarfarinTime in Range

10/8/2017

13

Drugs Supplements Foods/Beverages

• Acetaminophen

• Antibiotics (some)

• Amiodarone

• Aspirin or aspirin-containing products

• GI medications (some)

• Non-steroidal anti -inflammatory drugs (NSAIDs)

• Thyroid medications

• Bromelains

• Coenzyme Q10

• Danshen

• Dong quai

• Fish oil and omega-3 supplements

• Garlic

• Ginkgo biloba

• Ginseng

• St. John's wort

• Vitamin K

• Alcohol

• Foods high in vitamin K (eg, soybean and canola oils, spinach or broccoli)

• Garlic

• Black licorice

• Cranberries/juice

Interactions* With WarfarinPartial List

*The degree of interaction varies considerably.

New and Investigational Agents

for Stroke Prevention in AF

• Direct thrombin inhibitors– Dabigatran (RE-LY): FDA approved for prevention of

stroke in patients with AF

• Direct factor Xa inhibitors– Rivaroxaban (ROCKET AF): FDA approved for

prevention of stroke in patients with AF– Apixaban (ARISTOTLE)– Edoxaban (ENGAGE-AF)– Betrixaban (EXPERT)– YM150 (ONYX-2)

• Indirect Xa inhibitors– Idraparinux (BOREALIS-AF)

• Indirect inhibitors (eg, odiparcil)

US Food and Drug Administration. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm230241.htm

Accessed October 21, 2010. Usman MH, et al. Curr Treat Options Cardiovasc Med. 2008;10:388-397.

10/8/2017

14

XII

II

IX

XI

X

V

VIII VII

Tissue factor

Fibrinogen

Fibrin clot

Intrinsic pathwayExtrinsic pathway

Direct FXa inhibitors

(rivaroxaban, apixabanedoxiban)

Direct thrombin inhibitors

(dabigatran)

FXa = factor Xa

Adapted from: Nutescu EA, et al. Cleve Clin J Med. 2005;72(suppl 1):S2-S6.

New and Investigational AgentsMechanisms

NOAC SPAF Trials

Meta-Analysis of 71,683 Patients

10/8/2017

15

RE-LY

AF with at least 1 additional

risk factor for stroke

Randomized

(N ≈ 18 000)

• Age ≥75 years

• Age of 65 to 74 years plus diabetes mellitus, hypertension, or coronary artery disease

Dabigatran 110 mg BID Adjusted-dose

warfarin

Primary outcome: stroke or systemic embolism

Primary safety outcome: major bleeding

Other outcomes: stroke, systemic embolism, and death

2.0 year median follow-up

RE-LY = Randomized Evaluation of Long Term Anticoagulant Therapy

Connolly SJ, et al. New Engl J Med. 2009;361:1139-1151.

Blinded Unblinded/open label

Dabigatran 150 mg BID

or

RE-LYPrimary Outcome

Dabigatran

110 mg (n =

6015)

Dabigatran

150 mg (n =

6076)

Warfarin (

n = 6022)

Dabigatran 110

mg vs Warfarin

Dabigatran 150 mg

vs Warfarin

Annual Rate Annual RateAnnual

Rate

RR 95

% CIP Value

RR 95%

CIP Value

Stroke or

systemic

embolism

1.5% 1.1% 1.7%0.91 0.7

4-1.11

< .001 for

non-

inferiority,

.34

0.66 0.53-

0.82

<. 001 for

non-

inferiority, <

.001

Stroke 1.4% 1.0% 1.6%0.92 0.7

4-1.13.41

0.64 0.51-

0.81< .001

Connolly SJ, et al; and the RE-LY Steering Committee and Investigators. N Engl J Med. 2009;361:1139-1151.

10/8/2017

16

RE-LYBleeding Events

Dabigatran

110 mg

Dabigatran

150 mgWarfarin

Dabigatran 110 mg vs

Warfarin

Dabigatran 150 mg vs

Warfarin

Annual Rate Annual RateAnnual R

ateRR 95% CI P Value RR 95% CI P Value

Major 2.7% 3.1% 3.4%0.80 0.69-

0.93.003

0.93 0.81-

1.07.31

Life-

threatening

(major)

1.2% 1.5% 1.8%0.68 0.55-

0.83< .001

0.81 0.66-

0.99.04

Gastro-

intestinal

(major)

1.1% 1.5% 1.0%1.10 0.86-

1.41.43

1.50 1.19-

1.89< .001

Minor 13.2% 14.8% 16.4%0.79

0.74-0.84< .001

0.91

0.85-0.97.005

Major or

minor14.6% 16.4% 18.2%

0.78

0.74-0.83< .001

0.91

0.86-0.97.002

Connolly SJ, et al; the RE-LY Steering Committee and Investigators. N Engl J Med. 2009;361:1139-1151.

RE-LYMI, Death, and Net Clinical Benefit

Dabigatran

110 mg

Dabigatran

150 mgWarfarin

Dabigatran 110 mg

vs Warfarin

Dabigatran 150 mg

vs Warfarin

Annual Rat

e

Annual Rat

eAnnual R

ate

RR 95%

CI

P

ValueRR 95% CI

P

Value

MI 0.7% 0.7% 0.5%1.35

0.98-1.87.07

1.38

1.00-1.91.048

Death

from

any

cause

3.8% 3.6% 4.1%0.91

0.80-1.03.13

0.88

0.77-1.00.05

Net

clinical

benefit

7.1% 6.9% 7.6%0.92

0.84-1.02.10

0.91

0.82-1.00.04

Net clinical benefit includes vascular events, death and major bleed.

Connolly SJ, et al; the RE-LY Steering Committee and Investigators. N Engl J Med. 2009;361:1139-1151.

10/8/2017

17

Oral Factor Xa Inhibitors

Trial

AcronymDrug Dose Comparator N

Risk

factors

ROCKET-

AF (recently

concluded)

Rivaroxaban20 mga

QD

Warfarin

(INR 2-3)14 000 ≥2

ARISTOTLE Apixaban5 mg

BID

Warfarin

(INR 2-3)15 000 ≥1

ENGAGE-AF Edoxaban30 mg BID

60 mg* QD

Warfarin

(INR 2-3)16 500 ≥2

aAdjusted based on renal function.

Ongoing Phase III Trials for Prevention of Stroke and

Systemic Embolism in Patients With AF

Rivaroxaban Warfarin

Primary Endpoint: Stroke or non-CNS Systemic Embolism

INR target - 2.5

(2.0-3.0 inclusive)

20 mg daily15 mg for Cr Cl 30-49 ml/min

Atrial Fibrillation

Randomize

Double Blind /

Double Dummy

(n: 14,264)

Monthly Monitoring

Adherence to standard of care guidelines

Rocket AF Study Design

* Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%

Risk Factors• CHF • Hypertension • Age 75 • Diabetes OR• Stroke, TIA or

Systemic embolus

At least 2

or 3

required*

Rocket AF Investigators, AHA 2010

10/8/2017

18

ROCKET-AFPrimary OutcomesRivaroxaban

(n=7081)

Warfarin

(n=7090)

Hazard ratio

(95% CI)

p

Primary end point,

noninferiority

1.7 2.1 0.79 (0.66-0.96) <0.001

Vascular death,

stroke, embolism

3.1 3.6 0.86 90.74-0.99) 0.034

Hemorrhagic stroke 0.2 0.4 0.59 (0.37-0.93) 0.024

Ischemic stroke 1.3 1.4 0.94 (0.75-1.17) 0.581

Unknown stroke 0.0 0.1 0.65 (0.25-1.67) 0.366

Califf R. LBCT I: Abstract 21839. Presented at: American Heart Association Scientific Sessions 2010; Nov. 13-17, 2010; Chicago.

Days from Randomization

0

1

2

3

4

5

6

0 120 240 360 480 600 720 840 960

Cum

ula

tive

eve

nt ra

te (

%)

Warfarin

Rivaroxaban

ROCKET-AFPrimary Outcomes

HR (95% CI): 0.79 (0.66, 0.96)

P-value Non-Inferiority: <0.001

10/8/2017

19

ROCKET-AFBleeding Events

Rivaroxaban

(n=7081)

Warfarin

(n=7090)

Hazard ratio

(95% CI)

p

Major & nonmajor

bleeding

14.9 14.5 1.03 (0.96-1.11) 0.442

Major bleeding 3.6 3.4 1.04 (0.90-1.20) 0.576

Intracranial

hemorrhage

0.4 0.7 0.67 (0.47-0.94) 0.019

Califf R. LBCT I: Abstract 21839. Presented at: American Heart Association Scientific Sessions 2010; Nov. 13-17, 2010; Chicago.

WOEST

Cu

mu

lati

ve

in

cid

en

ce

(%

)

Cu

mu

lati

ve

in

cid

en

ce

(%

)

Safety outcomes Efficacy outcomes

WOEST study (N=573) compared safety outcomes with triple therapy (VKA +

clopidogrel + ASA) vs dual therapy (VKA + clopidogrel) 69% of WOEST patients

had AF, included prosthetic heart valves

10/8/2017

20

Pre-Randomization Choice of Duration of DAPT &

Thienopyridine: PIONEER AF-PCI

RANDOMIZE

1 mo: 16%

6 mos: 35%

12 mos: 49%

XARELTO® 15 mg qd*Clopi 95%, Ticag 4%, Prasugrel 1%

XARELTO® 15mg QDAspirin 75-100 mg qd

XARELTO® 2.5 mg bidClopi 95%, Ticag 4%,

Prasugrel 1%Aspirin 75-100 mg qd‡

VKA (target INR 2.0-3.0)Aspirin 75-100 mg qd

TTR 65%

VKA (target INR 2.0-3.0)Clopi 95%, Ticag 4%, Prasugrel

1%Aspirin 75-100 mg qd

≤ 72

hours

After

Sheath

removal

WOEST

Like

ATLAS

Like

Triple

Therapy

1 mo: 16%

6 mos: 35%

12 mos: 49%

Gibson et al. AHA 2016

2100 patients with NVAF

Coronary stenting

No prior stroke/TIA, GI bleeding, Hb<10, CrCl<30

Kaplan-Meier Estimates of First Occurrence of Clinically Significant Bleeding Events

TIM

I M

ajo

r, T

IMI

Min

or,

or

Ble

edin

g

Requirin

g M

edic

al A

ttention (

%)

697

Days

593 555 521 461 426 329

No. at risk

26.7%

Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug.

Clinically significant bleeding is the composite of TIMI major, TIMI minor, and BRMA.

Hazard ratios as compared to the VKA group are based on the (stratified, only for Overall, 2.5 mg BID/15 mg QD comparing VKA) Cox proportional hazards model.

Log-Rank P-values as compared to VKA group are based on the (stratified, only for Overall, 2.5 mg BID/15 mg QD comparing VKA) two-sided log rank test. Gibson et al. AHA 2016

18.0%

HR = 0.63 (95% CI 0.50-0.80)

ARR = 8.7

NNT = 12

706

697

636

593600

555

579

521

543

461

509

426

409

329

16.8%

p<0.000013

HR = 0.59 (95% CI 0.47-0.76)

ARR = 9.9

NNT = 11

696

697

628

593606

555

585

521

543

461

510

426

383

329

Riva + P2Y12 v. VKA + DAPT

HR=0.59 (95% CI: 0.47-0.76)

p <0.000013

ARR=9.9

NNT=11

Riva + DAPT v. VKA + DAPT

HR=0.63 (95% CI: 0.50-0.80)

p <0.00018

ARR=8.7

NNT=12

696

706

697

628

636

593

606

600

555

585

579

521

543

543

461

510

509

426

383

409

329

Riva + P2Y12

Riva + DAPT

VKA + DAPT

10/8/2017

21

Kaplan-Meier Estimates of First Occurrence of CV Death, MI or Stroke

Card

iovascula

r D

eath

, M

yocard

ial

Infa

rction,

or

Str

oke (

%)

Days

Riva + P2Y12

Riva + DAPT

VKA + DAPT

694

704

695

648

662

635

633

640

607

621

628

579

590

596

543

562

570

514

430

457

408

VKA + DAPT

Riva + DAPT

Riva + P2Y12

Riva + P2Y12 v. VKA + DAPT

HR=1.08 (95% CI: 0.69-1.68)

p=0.750

Riva + DAPT v. VKA + DAPT

HR=0.93 (95% CI: 0.59-1.48)

p=0.765

6.5%

5.6%

6.0%

Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug.

Composite of adverse CV events is composite of CV death, MI, and stroke.

Hazard ratios as compared to VKA group are based on the (stratified, only for the Overall, 2.5 mg BID/15 mg QD comparing VKA) Cox proportional hazards model.

Log-Rank P-values as compared to the VKA group are based on the (stratified, only for Overall, 2.5 mg BID/115 mg QD comparing VKA) two-sided log rank test.

6 Subjects were excluded from all efficacy analyses because of violations in Good Clinical Practice guidelines

No. at risk

Gibson et al. AHA 2016

Comparing efficacy for bleeding risk and CV event prevention with triple therapy

(ASA + VKA and P2Y12 Inhibitor) against Dual therapy with:

Dabigatran 110mg + P2Y12 Inhibitor

Or

Dabigatran 150mg + P2Y12 inhibitor

RE-DUAL PCI

10/8/2017

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Kaplan-Meier Estimates of Primary End-Point First Occurrence of Clinically Significant

Bleeding or Major Bleeding Events

P<0.001 for non-inferiority P<0.001 for non-inferiority

Kaplan-Meier Estimates of Secondary End-Point of MI, CVA, Systemic Embolic, Death or

Unplanned Revasculatization

P=0.005 for noninferiority

10/8/2017

23

WATCHMAN Device

Minimally Invasive, Local Solution• Available sizes: 21, 24, 27, 30, 33 mm

diameter

Intra-LAA design• Avoids contact with left atrial wall to help

prevent complications

Nitinol Frame• Conforms to unique anatomy of the LAA to

reduce embolization risk• 10 active fixation anchors - designed to

engage tissue for stability

Proximal Face• Minimizes surface area facing the left atrium

to reduce post-implant thrombus formation• 160 micron membrane PET cap designed to

block emboli and promote healing

PROTECT AF Clinical Trial Design

» Prospective, randomized study of WATCHMAN LAA Device vs. Long-

term Warfarin Therapy

» 2:1 allocation ratio device to control

» 800 Patients enrolled from Feb 2005 to Jun 2008

– Device Group (463)

– Control Group (244)

– Roll-in Group (93)

» 59 Enrolling Centers (U.S. & Europe)

» Follow-up Requirements

– TEE follow-up at 45 days, 6 months and 1 year

– Clinical follow-up biannually up to 5 years

– Regular INR monitoring while taking warfarin

» Enrollment continues in Continued Access Registry

10/8/2017

24

0.7

0.8

0.9

1.0

0 365 730 1095

Intent-to-TreatAll Stroke

ITT cohort: Non-inferiority

criteria met

Event-

free p

robabili

ty

Days244 147 52 12

463 270 92 22

WATCHMAN

Control

3000838-101

900 patient-year analysis

Events Total Rate Events Total Rate RR Non- SuperiorityCohort eve pt-yr (95% CI) (no.) pt-yr (95% CI) (95% CI) inferiority

600 14 409.3 3.4 8 223.6 3.6 0.96 0.927 0.488pt-yr (1.9, 5.5) (1.5, 6.3) (0.43, 2.57)

900 15 582.9 2.6 11 318.1 3.5 0.74 0.998 0.731pt-yr (1.5, 4.1) (1.7, 5.7) (0.36, 1.76)

Device Control Posterior probabilities

Randomization allocation (2 device:1 control)

WATCHMAN Device

10/8/2017

25

Take-Home Messages

• NoACs are noninferior to Warfarin for ischemic prevention but reduce major bleeding, ICH and mortality

• NoACs are the preferred therapy for patient with AF who starting primary stroke prevention

• NoACs may be considered for patients who are already taking a VKA

• Antiplatelet agents are not recommended for stroke prevention in AF

• Aspirin does not work in the seconary prevent of ischemic stroke in AF and carries a substantial bleeding risk

• Adjusted-dose warfarin remains the most effective therapy for stroke prevention

• Aspirin offers modest protection

• Poor outcomes from stroke off warfarin generally exceed those from warfarin-associated hemorrhage

• Emerging therapies have the potential to overcome many of warfarin’s limitations and improve the management of stroke prevention in patients with AF

Summary