Efficacy and Safety of the NOAC’s

R. Jeffrey Westcott, MD FACC FSCAI

Medical Director

Cardiac Catheterization Laboratory

Swedish Heart and Vascular Institute

Disclosures

• Medical Advisory Board

– Boston Scientific

– The Medicines Company

• Speakers Bureau

– Bristol-Myers Squibb

– Pfizer

– Daiichi Sankyo

The risk of stroke is increased ~5-fold in NVAF patients vs those without NVAF1,2

NVAF Is Associated With Significant Morbidity and Mortality

* P<0.001. AF=atrial fibrillation.

1. Wolf PA et al. Stroke. 1991;22:983-988. 2. Go AS et al. Circulation. 2014;129:e28-e292. 3. Marini C et al. Stroke. 2005;36:1115-1119.

Morbidity Mortality Stroke patients with NVAF are at increased

risk of death vs those without AF3

1-year

~52%

Rate of Death

Rate

, %

Incidence of Stroke According to Presence of NVAF (Framingham Heart Study)

Patients Without NVAF

2-Y

ea

r A

ge

-Ad

jus

ted

Inc

ide

nce

of

Str

oke

/10

00

Patients With NVAF

Risk Ratio: 4.8*

3

The CHADS2 and CHA2DS2-VASc Scoring Systems Assess Stroke Risk in Patients With NVAF

4

CHA2DS2-VASc* Stroke Risk Index2,3

Risk Factor Points

Congestive heart failure/LVD 1

Hypertension 1

Age ≥75 years 2

Diabetes mellitus 1

Stroke, TIA, or thromboembolism (prior) 2

Vascular disease† 1

Age 65 to 74 years 1

Sex category (ie, female gender) 1

Maximum score: 9

CHADS2 Stroke Risk Index1,2

Risk Factor Points

Congestive heart failure 1

Hypertension 1

Age ≥75 years 1

Diabetes mellitus 1

Stroke or TIA (prior) 2

Maximum score: 6

* A patient’s CHA2DS2-VASc score can either be the same as or higher than the CHADS2 score; it cannot be lower. † Prior myocardial infarction, peripheral artery disease, or aortic plaque LVD=left ventricular dysfunction; TIA=transient ischemic attack.

1. Gage BF et al. JAMA. 2001;285:2864-2870. 2. January CT et al. J Am Coll Cardiol. 2014. doi:10.1016/j.jacc.2014.03.022. 3. Lip GYH et al. Chest. 2010;137:263-272.

Stroke Risk Increases With Higher CHADS2 and CHA2DS2-VASc Scores in Patients With NVAF

5

As CHADS2 score increases, so does the risk of stroke1,2

Stroke Risk in National Registry of NVAF Patients by CHADS2 Score (N=1733)1,2

CHADS2 Score

Adjusted Stroke Rate*

%/year (95% CI)

0 1.9 (1.2–3.0)

1 2.8 (2.0–3.8)

2 4.0 (3.1–5.1)

3 5.9 (4.6–7.3)

4 8.5 (6.3–11.1)

5 12.5 (8.2–17.5)

6 18.2 (10.5–27.4)

CI=confidence interval.

1. Gage BF et al. JAMA. 2001;285:2864-2870. 2. January CT et al. J Am Coll Cardiol. 2014. doi:10.1016/j.jacc.2014.03.022. 3. Lip GY et al. Stroke. 2010;41:2731-2738.

* The adjusted stroke rate is the expected stroke rate per 100 patient-years from the exponential survival model, assuming that aspirin was not taken.

Risk of Stroke in NVAF Patients by CHA2DS2-VASc Score (N=7329)2,3

Better identifies low-risk patients with AF2

CHA2DS2-VASc Score

Adjusted Stroke Event 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 † Theoretical event rates without therapy; assuming that

oral anticoagulation provides a 64% reduction in risk.

What Does CHADS2 Really Tell Us?

CHADS2 Risk Calculator in Clinical Practice

CHADS2 Score Taking Warfarin Not Taking Warfarin

0 (2557) 0.25 (0.11-0.55) 0.49 (0.30-0.78)

1 (3662) 0.72 (0.50-1.03) 1.52 (1.19-1.94)

2 (2955) 1.27 (0.94-1.72) 2.50 (1.98-3.15)

3 (1555) 2.20 (1.61-3.01) 5.27 (4.15-6.70)

4 (556) 2.35 (1.44-3.83) 6.02 (3.90-9.29)

5 or 6 (241) 4.60 (2.72-7.76) 6.88 (3.42-13.84)

64% reduction on warfarin vs no antithrombotic therapy

2/3 of strokes on warfarin were at an INR <2

Event Rate (per 100 person-years) – 95% Confidence Interval

Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke pevntion in atrial fibrillation: how

well do randomized trials translate into clinical practice? JAMA. 2003;290:2685.

Aristotle – Efficacy of Apixaban vs Warfarin

0.00%

0.20%

0.40%

0.60%

0.80%

1.00%

1.20%

1.40%

1.60%

1.80%

Warfarin,n=9081

Apixaban,n=9120

265 1.27%

Stroke / Systemic Embolism Rates E

ve

nt

Rate

(%

/ye

ar)

Apixaban superior, p=0.01

HR (95% CI)

0.79 (0.66-0.95)

21% RRR

1.6%

212

ARISTOTLE – Major Bleeding Episodes

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Intracranial0.41 (0.30-0.57)

GI0.89 (0.70-1.14)

Fatal0.27 (0.13-0.53)

Intraocular1.42 (0.83-2.45)

Warfarin, n=9052

Apixaban, n=9088

0.93%

0.83%

0.24%

37 0.06%

10 22

0.21%

Event R

ate

s (

%/y

ear)

0.82%

125

Major Bleeding Episodes

0.33%

52

141

128

0.14%

32

HR (95% CI)

Major bleeding: fatal bleeding, critical site bleeding, Hb decrease >=2 g/dl,

transfusion >=2 units packed red cells.

Clinically Relevant Non-major Bleeding

0

0.5

1

1.5

2

2.5

3

3.5

CRNM

Warfarin

Apixaban

444

HR (95% CI): 0.70 (0.60-0.80)

p<0.0001

Event R

ate

s (

%/y

ear)

3.00 %/year

2.08 %/year

318

CRNM: Does not meet criteria for major bleeding and leads to hospital admission or

physician guided medical or surgical treatment for bleeding or results in a change in

antithrombotic therapy.

RE-LY Trial – Reduction in Stroke with Dabigatran

0

20

40

60

80

100

120

140

160

180

200

Stroke Ischemic Stroke HemorrhagicStroke

SystemicEmbolism

Warfarin (n=6022)

Dabigatran (n=6076)

Number of Events

186

122

134

103

45

12 21

13

HR: 0.64

95% CI (0.51-0.81)

HR: 0.75

95% CI (0.58-0.97)

HR: 0.26

95% CI (0.14-0.49)

HR: 0.64

95% CI (0.51-0.81)

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

Connolly SJ, et al. N Engl J Med. 2010;363(19):1875-1876.

RE-LY Trial – Bleeding Rates

0

500

1000

1500

2000

2500

Total Bleeds Major Bleeds Life ThreateningBleeds

Major GI Bleeds

Warfarin (n=6022)

Dabigatran (n=6076)

HR: 0.91

95% CI (0.85-0.96)

HR: 0.93

95% CI (0.81-1.07)

HR: 0.80

95% CI (0.66-0.98)

HR: 1.50

95% CI (1.17-1.85)

2166

1993

421 399

218 179 125 186

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

Connolly SJ, et al. N Engl J Med. 2010;363(19):1875-1876.

RE-LY – Intracranial Hemorrhages

0

10

20

30

40

50

60

70

80

90

100

Intracranial Hemorrhages

Warfarin (n=6022)

Dabigatran (n=6076)

90 (0.8%)

38 (0.3%)

HR 0.41 (95% CI: 0.28-0.60)

Event Rates Per 100 Patient Years

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

Connolly SJ, et al. N Engl J Med. 2010;363(19):1875-1876.

ROCKET AF Trial - Outcomes

0

50

100

150

200

250

300

Stroke HemorrhagicStroke

IschemicStroke

UnknownStroke Type

OtherSystemicEmbolism

Warfarin (n=7081)

Rivaroxaban (n=7090)

Primary composite endpoint vs warfarin: HR (95% CI): 0.88 (0.74, 1.03)

281

19 18

253

33 57

206 208

20 27

Patel MR, et al N Engl J Med. 2011;365(10):883-891.

ROCKET AF – Bleeding Rates

0

200

400

600

800

1000

1200

1400

1600

Major and NonmajorClinically Relevant

Major Nonmajor ClinicallyRelevant

Warfarin (n=7125)

Rivaroxaban 9n=7111)

HR 95% CI

1.03 (0.96, 1.11)

HR 95% CI

1.04 (0.90, 1.20)

HR 95% CI

1.04 (0.96, 1.13)

Patel MR, et al N Engl J Med. 2011;365(10):883-891.

1449 1475

386 395

1151 1185

TIMI 48 Study – Event Rates with Edoxaban

0

50

100

150

200

250

First stroke orSEE

Ischemic Stroke HemorrhagicStroke

SystemicEmbolism

Warfarin (n=7012)

Edoxaban 60 mg (n=7012)

232

135 144

182

75

13

39

8

97.5% CI

0.79 (0.63,0.99)

P=0.017

95% CI

0.62 (0.26,1.50)

95% CI

0.52 (0.36,0.77)

95% CI

0.94 (0.75,1.19)

Patel MR, et al N Engl J Med. 2011;365(10):883-891.

ROCKET AF – Major Bleeding

0

50

100

150

200

250

Bleeding Into aCritical Organ

Fatal Bleeding Transfusion GI Bleeding

Warfarin (n=7125)

Rivaroxaban (n=7111)

91

Patel MR, et al N Engl J Med. 2011;365(10):883-891.

133

55

27

221

140

183

149

Meta Analysis

0

500

1000

1500

2000

2500

3000

Stroke or SystemicEmbolism

Major Bleeding IntracerebralHemorrhage

Warfarin (n=29,285)

NOAC's (n=29,310)

982

2815

2587

419 199

778

Meta Analysis

982

778

0

200

400

600

800

1000

1200

Stroke or Systemic Embolism

Stroke or Systemic Embolism

Warfarin (n=29,285) NOAC's (n=29,310)

Meta Analysis

2815

2587

2450

2500

2550

2600

2650

2700

2750

2800

2850

Major Bleeding

Major Bleeding Episodes

Warfarin (n=29,285) NOAC's (n=29,310)

Meta Analysis

419

199

0

50

100

150

200

250

300

350

400

450

Intracerebral Hemorrhage

Intracerebral Hemorrhage

Warfarin (n=29,285) NOAC's (n=29,310)

Reversal Agents

• Indications

– Life threatening bleeding

– Uncontrolled bleeding

– Emergency surgery

– Urgent procedures

Reversal Agents

Coumadin prescribing information

Prothrombin complex concentrate (PCC), fresh frozen plasma, or

activated Factor VII treatment may be considered if the

requirement to reverse the effects of COUMADIN is urgent. A risk

of hepatitis and other viral diseases is associated with the use of

blood products; PCC and activated Factor VII are also associated

with an increased risk of thrombosis. Therefore, these

preparations should be used only in exceptional or life- threatening

bleeding episodes secondary to COUMADIN overdosage.

Reversal Agents

Swedish Epic order set

Reversal Agents

Swedish Epic order set

Reversal Agents

Swedish Epic order set

Reversal Agents

Swedish Epic order set

Dabigatran Reversal with Idarucizumab

Idarucizumab (Praxbind)

• Humanized monoclonal antibody fragment (Fab)

• Binds to dabigatran and its acylglucuronide metabolites

• Binding affinity higher to idarucizumab than to thrombin

• 5 gm dose

• Immediate reversal of anticoagulation due to dabigatran

Dabigatran Reversal with Idarucizumab

Factor Xa Inhibition Reversal

• Andexanet alpha

• Portola Pharmaceuticals

• Recombinant modified human factor Xa decoy protein.

• Catalytically inactive

• Binds factor Xa inhibitors at their active site with high

affinity

• Restores the activity of endogenous factor Xa

Anti Xa Agents Currently in Use

• Apixaban (eliquis)

• Rivaroxaban (xarelto)

• Edoxaban (savaysa)

• Low molecular weight heparin (lovenox)

• Fondaparinux (arixtra)

Factor Xa Inhibition Reversal

N Engl J Med 2015;373:2413-24

Factor Xa Inhibition Reversal

N Engl J Med 2015;373:2413-24

Factor Xa Inhibition Reversal

N Engl J Med 2015;373:2413-24

Factor Xa Inhibition Reversal

N Engl J Med 2015;373:2413-24