SESSION 3 Presenter Disclosure Information

SESSION 311 am – 12:30 pm

NOACs in Atrial Fibrillation

SPEAKERChristian T. Ruff, MD, MPH

Presenter Disclosure InformationThe following relationships exist related to this presentation:

► Christian T. Ruff, MD, MPH: Advisory Boards for Bayer; Boehringer IngelheimPharmaceuticals, Inc.; Daiichi Sankyo; and Portola. Contracted Research for Daiichi Sankyo.

Off-Label/Investigational Discussion

►In accordance with pmiCME policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations.

NOACs for Stroke Prevention in AF

Christian T. Ruff, MD, MPHTIMI Study Group

Brigham and Women’s HospitalHarvard Medical School

Boston, MA

Atrial Fibrillation: An Epidemic

Age-Adjusted Global Incidence AF Related Mortality

Sumeet S. Chugh et al. Circulation. 2014; 129:837-847.

100% 50% 0% -50% -100%

AFASAK-1 (671)

SPAF (421)

BAATAF (420)

CAFA (378)

SPINAF (571)

EAFT (439)

All Trials (n=6)

Warfarin Better Warfarin Worse

64%

Stroke Prevention in AF Warfarin vs. Placebo

Hart RG, et al. Ann Intern Med 2007;146:857-867. Gladston, DJ, et al. Stroke 2009;40:235-40

Subtherapeutic INR 29%

INR in range10%

No warfarin61%

AF Patients with Stroke with no Known Contraindication to Anticoagulation

Preventable Strokes

Dabigatran

Xa

IIa

TF/VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

Adapted from: Weitz JI, Bates SM. J Thromb Haemost 2005;3:1843-1853.

RivaroxabanApixabanEdoxaban

Non-Vitamin K Antagonist K Oral AnticoagulantsComparative PK/PD of NOACs

Dabigatran Rivaroxaban Apixaban Edoxaban

TargetIIa

(thrombin)Xa Xa Xa

Hours to Cmax 1-3 2-4 3-4 1-2

Half-life, hours 12-17 5-13 12 10-14

Renal Clearance, % 80 33* 27 50

Transporters P-gp P-gp P-gp P-gp

CYP Metabolism, %

None 32 <32 <4CYP = cytochrome P450; P-gp = P-glycoprotein

Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2013Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2011Weinz et al. Drug Dispos Metab 2009;37:1056–1064 ELIQUIS Summary of Product Characteristics. Bristol Myers Squibb/Pfizer EEIG, UK Matsushima et al. Am Assoc Pharm Sci 2011; abstractOgata, et al. J Clin Pharmacol 2010;50:743–753Mendell, et al. Am J Cardiovasc Drugs 2013;13:331–342Bathala, et al. Drug Metab Dispos 2012;40:2250–2255

*33% renally cleared; 33% excreted unchanged in urine

Pivotal Warfarin-Controlled TrialsStroke Prevention in AF

Trial of Warfarin vs. Placebo1989-1993

RE-LY(Dabigatran)

2009

ROCKET AF (Rivaroxaban)

2010

ARISTOTLE(Apixaban)

2011

ENGAGE AF-TIMI 48(Edoxaban)

2013

Warfarin vs. Placebo2,900 Patients

NOACs vs. Warfarin71,683 Patients

NOACs vs. Warfarin

Hemorrhagic

50%

Stroke

Ischemic

Similar

Major Bleeding

14% 25%

Ruff CT, et al. Lancet 2014;383:955-962

Fatal or Life-Threatening GI Bleeding

p=0.030 for HD-E vs. Warfarinp=0.000 for LD-E vs. Warfarinp=0.000 for HD-E vs. LD-E

p=0.043 for HD-E vs. Warfarinp=0.005 for LD-E vs. Warfarinp=0.037 for HD-E vs. LD-E

Major

Cu

mu

lati

ve h

azar

d

Years

Life‐Threatening or Fatal

Cu

mu

lati

ve h

azar

d

Years

Aisenberg J, et al. AHA 2015

≥66% 0.82 (0.71 - 0.95)

<66% 0.77 (0.65 - 0.92)

Experienced 0.85 (0.70 - 1.03)

Naive 0.75 (0.66 - 0.86)

3-6 0.80 (0.72 - 0.89)

2 0.86 (0.70 - 1.05)

0-1 0.75 (0.54 - 1.04)

>80 0.98 (0.79 - 1.22)

50-80 0.75 (0.66 - 0.85)

<50 0.79 (0.65 - 0.96)

Yes 0.86 (0.76 - 0.98)

No 0.78 (0.66 - 0.91)

Male 0.84 (0.75 - 0.94)

Female 0.78 (0.65 - 0.94)

≥75 0.78 (0.68 - 0.88)

<75 0.85 (0.73 - 0.99)

Center-Based TTR

VKA Status

CHADS2 Score

CrCl

Gender

Age

Risk Ratio (95% CI)

p=0.60

p=0.31

p=0.76

p=0.12

p=0.30

p=0.52

p=0.38

P-Interaction

Favors NOAC Favors Warfarin0.5 1 2

Prior Stroke or TIA

Yes

NoDiabetes

0.80 (0.69 - 0.93)

0.83 (0.74 - 0.93) p=0.73

Subgroups: Stroke or SEE


Center-Based TTR

VKA Status

CHADS2 Score

CrCl

Gender

Age

Favors NOAC0.2 0.5 1 2

Favors Warfarin

Prior Stroke or TIA

Diabetes

Male

Female

≥75

<75

Yes

No

≥66%

<66%

Experienced

Naive

3-6

2

0-1

>80

50-80

<50

Yes

No

p=0.022

p=0.78

p=0.09

p=0.57

p=0.70

p=0.29

p=0.28

0.93 (0.76 - 1.13)

0.69 (0.59 - 0.81)

0.87 (0.70 - 1.08)

0.84 (0.76 - 0.93)

0.86 (0.71 - 1.04)

0.88 (0.65 - 1.20)

0.60 (0.45 - 0.80)

0.85 (0.66 - 1.10)

0.91 (0.76 - 1.08)

0.74 (0.52 - 1.05)

0.89 (0.77 - 1.02)

0.85 (0.72 - 1.01)

0.90 (0.72 - 1.12)

0.75 (0.58 - 0.97)

0.93 (0.74 - 1.17)

0.79 (0.67 - 0.94)

Risk Ratio (95% CI) P-Interaction

p=0.12

0.90 (0.78 - 1.04)

0.71 (0.54 – 0.93)

Subgroups: Major Bleeding


What is the definition of non-valvular AF?

Have NOACs expanded our treatment of vulnerable patients [frail / fall risk] previously not prescribed warfarin?

Can we use aspirin to prevent strokes?

Subclinical AF: How much AF warrants anticoagulation?

Do we need to monitor NOACs levels or anticoagulant activity?

Are there relevant drug interactions to be aware of when using NOACs?

How do we optimize combination antithrombotic therapy in patients with AF + ACS/PCI?

How to prevent and manage bleeding with NOACs and the role for specific reversal agents?

Translating Clinical Trials into Real World Practice:Current Challenges & Opportunities

ESC 2016 Update AF Guidelines

What do Guidelines Say About “Non-Valvular AF”

Absence of moderate or severe rheumatic valvular disease (mitral stenosis) or mechanical heart valve.

Kirchhof P, et al. Eur Heart J. 2016 [Epub ahead of prin]January CT et al. J Am Coll Cardiol. 2014;64:e1-76

2014 AHA/ACC/HRS AF Guidelines

Absence of rheumatic mitral stenosis, a mechanical or bioprosthetic heart valve, or mitral valve repair.

Hohnloser SH and Lopes RD. Eur Heart J. 2014;35:3323-5Renda G et al. J Am Coll Cardiol. 2016;67(13S):2194-2194.

Outcomes in Patients with and without Valvular Heart Disease: Meta-Analysis

Stroke or Systemic Embolism

Major bleeding

Rivaroxaban1

Apixaban1

Dabigatran 150 mg1

Dabigatran 110 mg1

Rivaroxaban1

Apixaban1

Dabigatran 150 mg1

Dabigatran 110 mg1

Interaction P value

P=NS

P=NS

P=NS

P=NS

P=NS

P=NS

P=NS

P=0.034

0.5 2.01.0

Nonvalvulardisease

Valvular disease

Edoxaban2 P=NS

Edoxaban2P=NS

Many patients with clinically significant valvular heart disease were included in clinical trials.

If the valve disease itself necessitates anticoagulation use VKA

If the valve disease does not warrant anticoagulation, you can use any anticoagulant (VKA or NOAC)

Conclusions

Eikelboom JW et al. N Engl J Med. 2013;369:1206-14.

Thrombus on prosthetic valve

Phase 2 dose-finding trial of dabigatran in pts with mechanical valves,150-330 mg bid, adjusted based on renal function and results of Hemoclot

Trial terminated early after enrolment of 252 pts because excess thromboembolic and bleeding events with dabigatran. Ischemic/unspecified stroke occurred in 9 pts with dabigatran and in no warfarin pts; major bleeding in 7 (4%) and 2 pts (2%).

Most clinical outcome events occurred in the group enrolled just after valve replacementrather than those enrolled ≥3 months after surgery

100

0.8

0.6

0.4

0.2

0

First Bleeding Event

0 50 100 150 200 250 300 350 400

Days

Dabigatran

Warfarin

Event-free survival from the first bleeding event (P=0.01)

RE-ALIGN extension trial

100

0.8

0.6

0.4

0.2

0

Pro

bab

ility

of

No

Eve

nt

First Thromboembolic Event

0 50 100 150 200 250 300 350 400

Days

DabigatranWarfarin

Event-free survival from stroke, systemic embolism, TIA, MI or death (P=0.24)

RE-ALIGN extension trial

RE-ALIGN: Warfarin vs. Dabigatran in Patients with Mechanical Heart Valves

Tissue factor

Xa

Thrombin

Contact

(stents, valves,catheters)

VIIaXIIaXIa

(plaque rupture)

Clot formation

Intrinsic Pathway

Common Pathway

Extrinsic Pathway

Activation of the Coagulation Cascade Failure to Treat Patients with AF

Hsu JC, et al. JAMA Cardiol 2016; 1(1):55-62

NCDR PINNACLE Registry

Benefit of NOACs in Patients at Risk of Falls

Steffel J, et al. J Am Coll Cardiol. 2016; 68(11):1169-1178

AVERROES: The End for Aspirin

Stroke or SEE Major Bleeding

HR 0.45 (0.32-0.62) HR 1.13 (0.74-1.75)

Aspirin

Apixaban

P<0.001

0 3 6 9 12 18

0.05

0.04

0.03

0.02

0.01

0.00

Aspirin

Apixaban

P<0.001

0 3 6 9 12 18

0.020

0.015

0.010

0.005

0.000

Connolly SJ, et al. N Engl J Med 2011;364(9):806-17

We are still failing to anticoagulate high-risk patients.

Frailty / fall risk is not an appropriate reason to withhold anticoagulation: The have the greatest absolute benefit!

Aspirin has no role for stroke prevention in patients with AF. It is not effective and not any safer than NOACs.

Conclusions

Healey JS, et al. NEJM. 2012; 366:120-129

Str

ok

e o

r S

yste

mic

Em

bo

lism

Years

Atrial Tachyarrhythmia > 6 min ≤ 3 Months After Pacemaker or Defibrillator Implantation

Subclinical AF and Stroke Risk

Temporal Relationship Between SCAF & Stroke

Brambatti M, et al. Circulation. 2014;129(21):2094-2099

Relative risk of ischemic stroke appears increased for SCAF.

There is a gradient of absolute risk that correlates with AF burden.

Large clinical trials are needed to define optimal treatment of these patients.

Subclinical AF and Stroke

Eikelboom JW, et al. Circulation. 2011;123:2363-72Reilly , PA ,et al. J Am Coll Cardiol. 2014;63:321-8

Dabigatran 110 mg vs. warfarin

Dabigatran 150 mg vs. warfarin

Total rate (% per year)

# PTS D110 D150 WAR

Overall 18113 2.87 3.31 3.57

Age <65 2971 0.82 0.89 2.43

Age 65–74 7884 2.29 2.6 3.25

Age ≥75 7258 4.43 5.1 4.37 0.0003 0.0001

Dabigatran trough concentration steady state (ng/mL)

16

14

12

10

8

6

4

2

00 50 100 150 200 250 300

Pro

bab

ilit

y m

ajo

r b

leed

(%

)

65 years75 years85 years

16

14

12

10

8

6

4

2

00 50 100 150 200 250 300

Pro

bab

ilit

y is

chae

mic

str

oke

/SE

E (

%)

0.50 1.00 1.50Dabigatran better Warfarin better

0.50 1.00 1.50

Dabigatran better Warfarin better

P-value (interaction)

P-value (interaction)

Do We Need to Monitor NOAC Levels? Dose Reductions

RE‐LY1 ARISTOTLE3 ENGAGE‐AF4

•60→30 mg QD or 30→15 mg QD for:

– Creatinineclearance30–50 mL/min

– body weight≤60 kg

– Use of quinidine, verapamil or dronedarone

• 5→2.5 mg BID for ANY TWO of:

– Age≥80 years

– body weight≤60 kg

– Serum creatinine≥1.5 mg/dL

•None

ROCKET‐AF2

• 20→15 mg QD for:

– Creatinineclearance<30–49 mL/min

1. Connolly et al. N Engl J Med 2009;361:1139–11512. Patel et al. N Engl J Med 2011;365:883–8913. Granger et al. N Engl J Med 2011;365:981–9924. Giugliano RP et al. N Engl J Med 2013;369:2093-2104

Stroke or SEE (% / Year)

1.29

2.21

1.00

1.79

0.0

0.5

1.0

1.5

2.0

2.5

48.5Edox Conc (ng/mL) 0.85Anti-Fxa (IU/mL)

No Edoxaban Dose Reduction Edoxaban Dose Reduced

Warfarin HD Edox60 mg


NANA

34.60.64

NANA

Higher-Dose Edoxaban vs. WarfarinNo Dose Reduction: HR 0.78 (0.61 - 0.99)Dose Reduction: HR 0.81 (0.58 - 1.13)

Pinteraction = 0.85

HD = Higher-DoseEdox = Edoxaban

3.02

4.85

2.663.05

0.0

1.0

2.0

3.0

4.0

5.0

6.0

48.5Edox Conc (ng/mL) 0.85Anti-Fxa (IU/mL)




NANA

34.60.64

NANA

HD = Higher-DoseEdox = Edoxaban

Major Bleed (% / Year)Higher-Dose Edoxaban vs. WarfarinNo Dose Reduction: HR 0.88 (0.76 - 1.03)Dose Reduction: HR 0.63 (0.50 - 0.81)

Pinteraction = 0.02

48.5 ± 45.8

34.6 ± 30.9

0

10

20

30

40

50

60

0.85 ± 0.76

0.64 ± 0.54

0.00

0.20

0.40

0.60

0.80

1.00

ng

/ mL

IU /

mL

No DR60 mg

DR30 mg

No DR60 mg

DR30 mg

Mean Edoxaban Trough Concentration

Mean Trough Anti-FXa Activity

Edoxaban Concentration & Anti-FXa Activity

DR, dose reduction Ruff CT, Lancet 2015;385:2288–95

Stroke or SEE (% / Year)

1.29

2.21

1.00

1.79

1.38

2.36

0.0

0.5

1.0

1.5

2.0

2.5

48.5 24.5Edox Conc (ng/mL) 0.85 0.44Anti-Fxa (IU/mL)



LD Edox30 mg


LD Edox15 mg

NA

NA

34.6 16.0

0.64 0.35NA

NA

HD = High DoseLD = Low DoseEdox = Edoxaban

Ruff CT, Lancet 2015;385:2288–95

~40%

Drug‐drug Interactions With NOACsMechanism of Action Dabigatran Rivaroxaban Apixaban Edoxaban

Dronedarone P‐gp inhibitorNo specific

recommendationsNo specific

recommendations

Clarithromycin Strong inhibition of CYP3A4 and P‐gpNo specific

recommendations

Itraconazole Strong inhibition of CYP3A4 and P‐gp Avoid useNo specific

recommendations

Ketoconazole Strong inhibition of CYP3A4 and P‐gpWith CrCl 30‐50

ml/min reduce dose to 75 mg twice daily

Avoid useNo specific

recommendations

Ritonavir Strong inhibition of CYP3A4 and P‐gp Avoid useNo specific

recommendations

Carbamazepine Strong inducer of CYP3A4 and P‐gp Avoid use Avoid use Avoid useNo specific

recommendations

Phenytoin Strong inducer of CYP3A4 and P‐gp Avoid use Avoid use Avoid useNo specific

recommendations

Rifampin Strong inducer of CYP3A4 and P‐gp Avoid use Avoid use Avoid use Avoid use

St. John’s wort Strong inducer of CYP3A4 and P‐gp Avoid use Avoid use Avoid useNo specific

recommendations

Kovacs RJ, et al. J Am Coll Cardiol. 2015.Red: Avoid Yellow: Reduced Dose Green: OK to use

Dosing based on clinical features alone optimizes efficacy/safety for most patients.

Dose adjustment based on drug levels or anticoagulant actively will be challenging and needs to be prospectively tested.

Systemic under-dosing of NOACs a major problem that will lead to unnecessary strokes.

Drug-drug interactions far less common than warfarin :

Know drug classes to potentially avoid [anticonvulsants, antivirals, and antifungals]Others don’t warrant dose reduction on their own.

Conclusions

Providing the best protection for patients with AF and PCI/ACS

NVAF PCI/ACS NVAF and PCI/ACS

BOTH anticoagulant and dual antiplatelet

therapy = ‘triple therapy’

?

Antiplatelet therapy

High sheer stress thrombosis – platelet mediated in the arteries

Dual antiplatelet therapy superior to ASA alone

Anticoagulant therapy

Low sheer stress thrombosis in left atrium

NVAF and ACS / PCI:A Broad Spectrum of Options

• ASA alone• Clopidogrel alone• Ticagrelor alone• Warfarin alone• NOAC alone

• ASA + warfarin• Clopidogrel + warfarin• Prasugrel + warfarin• Ticagrelor + warfarin• ASA + NOAC• Clopidogrel + NOAC (low dose)• Clopidogrel + NOAC (high dose)• Prasugrel + NOAC• Ticagrelor + NOAC

• ASA + clopidogrel + warfarin• ASA + prasugrel + warfarin• ASA + ticagrelor + warfarin• ASA + clopidogrel + NOAC

(low dose)• ASA + clopidogrel + NOAC

(high dose)• ASA + prasugrel + NOAC• ASA + ticagrelor + NOAC

• ASA + clopidogrel• ASA + prasugrel• ASA + ticagrelor

RE-LY: Bleeding with Antiplatelet Therapy

Dans AL, et al. Circulation. 2013; 127:634-640

WARFARIN

Dabi 150

Dabi 110

None

ASA

ASA + Clopidogrel

None

ASA

ASA + Clopidogrel

None

ASA

ASA + Clopidogrel

0 5 10

2.84.6

6.3

HR=1.50 (95%CI: 1.22, 1.86)HR=2.34 (95%CI: 1.53, 3.57)

HR=1.81 (95%CI: 1.46, 2.24)HR=2.16 (95%CI: 1.34, 3.47)

HR=1.53 (95%CI: 1.21, 1.92)HR=2.39 (95%CI: 1.53, 3.74)

2.64.3

5.52.2

3.85.4

Major Bleeding*

*Adjusted for age, gender, warfarin experience, SBP, CAD, CHF, TIA, HTN, DM, CrCl, Statins

Avoid or Limit Triple Therapy

Bhatt DL. J Am Coll Cardiol. 2015;65:1630-2

Kirchhof P, et al. Eur Heart J. 2016 [Epub ahead of print]

How to Approach Combination Antithrombotic Therapy - ACS

Patients With Atrial Fibrillation Undergoing Coronary Stent Placement: PIONEER AF-PCI

Primary endpoint: TIMI major + minor + bleeding requiring medical attention

Secondary endpoint: CV death, MI, and stroke (Ischemic, Hemorrhagic, or Uncertain Origin)

*Rivaroxaban dosed at 10 mg once daily in patients with CrCl of 30 to <50 mL/min.†Alternative P2Y12 inhibitors: 10 mg once-daily prasugrel or 90 mg twice-daily ticagrelor.‡Low-dose aspirin (75-100 mg/d). ∆ Open label VKA

2100 patients with NVAF

Coronary stenting

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

RANDOMIZE

1,6, or 12 months

Rivaroxaban 15 mg qd*Clopidogrel 75 mg qd†

Rivaroxaban 15mg QDAspirin 75-100 mg qd

Rivaroxaban 2.5 mg bidClopidogrel 75 mg qd†

Aspirin 75-100 mg qd‡

VKA∆(target INR 2.0-3.0)

Aspirin 75-100 mg qd

VKA∆ (target INR 2.0-3.0)Clopidogrel 75 mg qd†

Aspirin 75-100 mg qd

≤72hours

AfterSheath removal

1,6, or 12 months

End oftreatment12 months

WOEST Like

ATLAS Like

TripleTherapy

Gibson et al. AHA 2016

Pre randomization MD Choice

Pre randomization MD Choice

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

TIM

I Maj

or,

TIM

I Min

or,

or

Ble

edin

g

Req

uir

ing

Med

ical

Att

enti

on

(%

)

697

Days

593 555 521 461 426 329VKA + DAPT

No. at risk

VKA + DAPT

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

VKA + DAPT

Riva + DAPT

18.0%

p<0.00018

HR = 0.63 (95% CI 0.50-0.80)ARR = 8.7NNT = 12

706697

636593

600555

579521

543461

509426

409329

Riva + DAPTVKA + DAPT

VKA + DAPT

Riva + P2Y12

16.8%

p<0.000013

HR = 0.59 (95% CI 0.47-0.76)ARR = 9.9NNT = 11

696697

628593

606555

585521

543461

510426

383329

Riva + P2Y12

VKA + DAPT

Riva + P2Y12

VKA + DAPT

Riva + DAPT

Riva + P2Y12 v. VKA + DAPT

HR=0.59 (95% CI: 0.47-0.76)p <0.000013ARR=9.9NNT=11

Riva + DAPT v. VKA + DAPTHR=0.63 (95% CI: 0.50-0.80)p <0.00018ARR=8.7NNT=12

696706697

628636593

606600555

585579521

543543461

510509426

383409329

Riva + P2Y12


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

Car

dio

vasc

ula

r D

eath

, Myo

card

ial

Infa

rcti

on

, or

Str

oke

(%

)

DaysRiva + P2Y12


694704695

648662635

633640607

621628579

590596543

562570514

430457408

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 + DAPTHR=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

In patients who require anticoagulation for AF, a less potent / shorter duration of antiplatelet therapy may offer the best net clinical benefit.

More data is needed to define an “optimal” antithrombotic regimen but general principle is that anticoagulation protects against stroke and coronary events while antiplatelet inferior for stroke prevention.

Conclusions

Prevention

Utility of coagulation testing

How to manage bleeding

Role of specific reversal agents / antidotes

Managing Bleeding with NOACs

Ruff CT, et al. Lancet. 2014; 383:955-962

How Frequent is Bleeding with NOACs?

2.39

2.80

1.170.92

0.320.66

0.00

1.00

2.00

3.00

4.00

5.00

NOACs Warfarin

Major Bleeding

GI Bleeding

ICH

71,683 Patients: 4 Phase III AF NOAC Trials

% /

Yea

r

Discontinuing NOACs Prior to Procedures

Minor Bleeding RiskEndoscopy with biopsy, prostate or bladder biopsy, EPS/RFA for SVT, angiography, pacemaker or implantable cardioverter defibrillator (unless complex anatomic setting, such as congenital heart disease)

Major Bleeding RiskComplex left-sided ablation (AF, VT), spinal or epidural anesthesia, lumbar diagnostic puncture, thoracic surgery, abdominal surgery, major orthopedic surgery, liver biopsy, TURP, kidney biopsy

Heidbuchel H, et al. Europace. 2015; 17(10):1467-1507

Coagulation Tests

TestApixaban/Rivaroxaban/Edoxab

anDabigatran

Qualitative Present / Absent

PT rivaroxaban>edoxaban>apixaban[sensitivity depends on reagents]

TT>aPTT

Quantitative testChromogenic anti-FXa

[requires specific calibration to drug]Dilute TT, chromogenic anti-FIIa

[requires specific calibration]

Normal PT or aPTT does not guarantee absence of anticoagulant effect

Quantitative tests are not standardized or approved

Tripodi A, et al. Thromb Haemost 2011; 105:735-736Barrett YC, et al. Thromb Haemost 2010; 104:1263-1271van Ryn J, et al. Thromb Haemost 2010; 103:1116-1127Stangier J, et al. Br J Clin Pharmacol 2007; 64:292-303Cuker A, et al. JACC 2014; 64(11):1128-1139

Non-Specific Reversal Agents

Agent Clotting Factors Replaced Dose

4 Factor-PCC Factors II, VII, IX, X 25-50 units/kg

3 Factor-PCC Factors II, IX, X 25-50 units/kg

aPCC Factors II, VIIa, IX, X 80 units/kg

rFVIIa FVIIa 90 ug/kg

Only After D/C drug and Supportive Care (fluids / transfusions)

Specific NOAC Reversal Agents

Ruff CT, et al. Circulation. 2016 ; 134(3):248-261

Group A: Uncontrolled bleeding + dabigatran-treated

Group B: Emergency surgery or procedure + dabigatran-treated

N = 494

0–15 min 90 days follow-up

Hospital arrival

5 g idarucizumab (2 x 2.5 g

intravenously)

Pre-2nd vial 2 h 4 h 12 h 24 h 30 d 90 dPre-1st vial 1 hBlood

samples

*Connolly S,et al. N Engl J Med. 2009; 361:1139–51.Pollack C, et al. Thromb Haemost. 2015;114:198–205.dTT, diluted thrombin time; ECT, ecarin clotting time.

~20 min

Reverses up to the 99th percentile of dabigatran levels

measured in RE-LY®*

Multicenter, Ongoing, Open-label, Single-arm Phase III study

Primary endpoint: Maximum reversal within 4 h based on dTT, ECT

10th/90th percentiles 5th/95th percentilesMedian and 25th/75th percentiles

RESULTS: Diluted Thrombin Time (dTT) - Assessment ofReversal of Dabigatran Anticoagulation with Idarucizumab

ULN, upper limit of normal

Assay ULN

Similar results were also obtained with Ecarin Clotting Time (ECT)

Group B: Peri-procedural Hemostasis191 of 196 (97.4%) patients underwent surgery/procedures Median time from administration of first vial to procedure was 1.6 hours Adequacy of hemostasis during surgery determined locally

Mortality (Kaplan-Meier Survival)

Follow-up Group A (N = 298)

Group B (N = 196)

30 days

Patients at risk, n 250 164

Mortality, % 12.3 12.4

90 days

Patients at risk, n 149 105

Mortality, % 18.7 18.5

Day 1

ANNEXA-4 Study Design

Patient with acute major bleed, meeting inclusion criteria

Patient ScreeningIV

Bolus2-hour

IV Infusion

Safety follow-up visit

Efficacy Measurements

Change in anti-FXa activity

Clinical hemostatic efficacy through 12 hours

Day 30Day 3

If last dose of fXa inhibitor was within 18 hours

AndexanetTreatment

Bleeding and Laboratory Assessment

Assessments:

Safety Measurements

Thrombotic events

Antibodies to FX, FXa, andexanet

30-day mortality

After end of infusion

1 hr 4 hr 8 hr 12 hr

Connolly S, et al., N. Engl. J. Med. 2016

ANNEXA-4 Dose Selection

Acute major bleeding ≤ 18 hours of last dose ofapixaban, edoxaban, rivaroxaban, or enoxaparin

Andexanet IV bolus and 2 hour infusion

Pts on apixaban or>7 h from last rivaroxaban dose

Bolus 400 mg+

Infusion 480 mg @ 4 mg/min

Pts on enoxaparin or edoxaban or ≤ 7 h from last rivaroxaban dose

Bolus 800 mg+


Pts on enoxaparin, edoxaban or≤7 h from last rivaroxaban dose

Bolus 800 mg+


Connolly S, et al., N. Engl. J. Med. 2016

ANNEXA-4: Anti-FXa Activity

Connolly SJ, et al. N Engl J Med 2016;375:1131-41

ANNEXA-4: Clinical Hemostatic Efficacy


ANNEXA-4: Death or Thrombotic Events


60

BASELINE (Pre-edoxaban)

ANTICOAGULATED(Pre-PER977, 2.75 hrs 60 mg edoxaban p.o.)

REVERSED(1 hr post 100 mg i.v. bolus PER977)

Scale Bar: 1 inch

Pre-PER977, 2.75 hrs post 60 mg p.o.

edoxaban

Pre-edoxabanbaseline

1 hr post 100 mg i.v.

PER977

0

50

100

150

200

250

300

60mg POedoxaban+ IV saline

placebo

60mg POedoxaban+ 25mg IVPER977

60mg POedoxaban+ 100mg

IVPER977

60mg POedoxaban+ 300mg

IVPER977

Native

Fib

rin

dia

met

er [

nm

]

******

Ansell JE, et al. NEJM. 2014; 371(22):2141-2142

Ciraparantag Anticoagulation Bleeding Algorithm

Kirchhof P, et al. Eur Heart J. 2016 [Epub ahead of print]

Management of NOAC Treated Patients who Require Invasive Procedures

Ruff CT, et al. Circulation. 2016 ; 134(3):248-261

Serious bleeding is uncommon with NOACs50% less compared to warfarin

Many bleeds are preventableStop unnecessary antiplatelet agents and NSAIDs

For most bleeds: temporarily stopping anticoagulation and supportive measures are all that is needed

Laboratory coagulation tests have limited utility

PCCs are the preferred non-specific reversal agent

Specific antidotes available for dabigatran and likely soon to be available for Fxa inhibitors: trauma, urgent surgery, stroke requiring lysis

Anticoagulation should be restarted in the majority of patients who experience a bleed once stabilized

Conclusions

Heart Failure (HF) has reached epidemic proportions - 23 million individuals worldwide- Incidence increasing, especially among elderly

½ of patients have reduced ejection fraction (HFrEF)

Significant morbidity, mortality, and cost- 1 million HF hospitalizations/yr- Cost to US health system 39 billion dollars annually

(expected to increase)

Thrombotic complications- HF 2nd most common cause of cardioembolic stroke- Major risk factor for DVT & PE (OR 2.6)

Heart Failure

Go et al. Circulation 2014;129:e28-e29.Pullicino, et al. Cerebrovasc Dis. 2008; 26(3):322-7Goldhaber, et al. Am J Cardiol. 2004; 93:259-262Alikhan, et al. Am J Med. 2008;121:935-942Howell MD, et al. J Clin Epidemiol 2001;54:810-816

WARCEF: Efficacy and Safety Endpoints

Homma et al. N Engl J Med. 2012;366:1859-1869.

Warfarin vs. Aspirin in Patients with HF & NSR

COMMANDER HF

Zannad F, et al. Eur J Heart Fail. 2015;17(7):735-742

Patients with HF and CAD following HF exacerbation

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