How to Select an Oral Anticoagulant - CHI Memorial ... · How to Select an Oral Anticoagulant Vinay Madan MD February 27, ... Targets of Oral Anticoagulants Common ... 2 Score Patients,

How to Select an Oral Anticoagulant

Vinay Madan MDFebruary 27, 2016

Southeast Regional Heart and Vascular Symposiumfor Primary Care Providers

Objectives

1. Review the evidence base and rationale forthromboprophylaxis in atrial fibrillation (AF)with warfarin

2. Review the evidence base supporting use of the novel oral anticoagulants (NOACs) in AF

3. Identify key patient characteristics that impact choice of an oral anticoagulant in practice

Indications for OAC

• Atrial fibrillation

• Venous thromboembolism (VTE)

• Prophylaxis of VTE

• Prosthetic heart valve

• Prophylaxis of systemic thromboembolism in patients at high risk– Post myocardial infarction

– Cardiomyopathy

– Secondary prevention after stroke

Atrial Fibrillation

Left atrial appendage thrombus

Atrial Fibrillation: A growing epidemic

The current estimated prevalence is ~3%, or 7-8 million people with AF in 2015

Year

Pro

ject

ed P

erso

ns W

ith

AF,

mill

ion

12.1

15.915.2

14.3

13.111.7

10.28.9

7.76.7

5.95.1

11.711.1

10.39.4

8.47.5

6.86.1

5.65.1

Miyasaka, Y, et al. Circulation. 2006;114:119-125

Continued increase in AF incidence rateNo increase in AF incidence rate


Lifetime risk of developing AF is now

1 in 4 for those individuals ≥ 40 years old

Atrial Fibrillation is associated with a high morbidity

• Number one reversible cause of stroke in the US

• Responsible for 1 in 5 of all strokes

• Strokes associated with AF are larger, more fatal, and more likely to recur than non-AF strokes

Risk Stratification:Embolic Risk

Risk Stratification:Embolic Risk

CHADS vs. CHADS-VAScComparative rates of stroke/SE/death

Ng HK, et al. Cardiol Ther. 2013/2: 135-149.

Risk Stratification:Bleeding Risk

WarfarinAn effective antithrombotic therapy for > 60 years

• First introduced as a pesticide against mice and rats in 1948

• Found to be effective and relatively safe for preventing thrombosis in many disorders

• Approved for use as a medication in 1954

Synthesis of Non

Functional Coagulation

Factors

Vitamin K

VII

IX

X

II

Warfarin

WarfarinMechanism of action

Antagonismof

Vitamin K

Vitamin-K dependent

Coagulation Factors

Targets of Oral Anticoagulants

CommonPathway

IX

VIII

Xa

Thrombin

Fibrin

ThrombinActivity

Contact

PropagationPhase

PlateletSurface

Fibrinogen

Warfarin

InitiationPhase

TF VIIa

Stroke Prevention in Atrial FibrillationWarfarin vs. Placebo (6 trial; n = 2900)

Warfarin better Control better

AFASAK

SPAF

BAATAF

CAFA

SPINAF

EAFT

100% 50% 0 -50% -100%

Aggregate

RRR of stroke: 64%

RRR of stroke: 64%

RRR in mortality: 26%

RRR in mortality: 26%

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

Slow onset

Slow offset

Food/drug interactions

Narrow therapeutic

window

Heparin bridging

Unpredictable dose response

Frequent monitoring

Complicates peri-procedural

management

Limitations of Warfarin

Warfarin Dosing Is Complex

• Age, sex• Body surface area or weight• Amiodarone• Other drugs (eg, acetaminophen)• Race• Plasma vitamin K level• Decompensated CHF • Active malignancy• Genetic status

CHF = congestive heart failure; CYP2C9 = cytochrome P450 2C9; INR = international normalized ratio; VKORC1 = vitamin K epoxide reductase complex subunit 1

Other factors(up to 40%)

Age, sex, weight

(10–20%)

CYP2C9(up to 15%)

VKORC1(up to 25%)

Hazards of Warfarin

Budnitz DS, et al. N Engl J Med. 2011;365:2002-2012

Medication

Annual National Estimate of Hospitalizations

(N = 99,628)

Proportion of Emergency Department Visits Resulting

in Hospitalization

Most commonly implicated medications no. % %

Warfarin 33,171 33.3 46.2

Insulins 13,854 13.9 40.6

Oral antiplateletagents 13,263 13.3 41.5

Oral hypoglycemicagents 10,656 10.7 51.8

Opioid analgesics 4778 4.8 32.4

Antibiotics 4205 4.2 18.3

Hazards of Warfarin

Budnitz DS, et al. N Engl J Med. 2011;365:2002-2012

Adverse EventEstimate of

Hospitalizations, % EDVisits Resulting in

Hospitalization, %Hematologic agents

Intracranial hemorrhage 5.6 99.7

Hemoptysis 2.0 73.6

Gastrointestinal hemorrhage 40.8 84.7

Genitourinary hemorrhage 4.7 42.4

Epistaxis 6.1 10.6

Skin or wound hemorrhage 6.8 24.5

Other type of hemorrhage 5.3 27.5

Elevated INR, abnormal laboratory values, or drug toxicity not otherwise described

23.7 59.5

Hazards of WarfarinMortality rate

~ 50%

1

Slide 20

1 Vinay Madan, 2/21/2016

Undertreatment with OACGARFIELD Registry

Overall(n = 10,607)

0(n = 857)

1(n = 3688)

2(n = 3302)

3(n = 1716)

4(n = 757)

5(n = 238)

6(n = 49)

NoneAP2Fxa/DIIVKAVKA+AP

10.6 7.1 8.4 11.5 12.2 16.2 14.7 16.3

45.2

35.143.2

47.8 50.1 45.742.4

32.7

25.3

30.8

27.923.4 21.9 22.2

26.1 22.4

14.424.4

16.7 12.6 10.5 8.6 13.9 14.3

CHADS2 Score

Pat

ient

s, %

100

80

60

40

20

0

“Novel” or “Non-Vitamin K” Oral Anticoagulants (NOACs)

Factor Xa Factor IIa (Thrombin)

RivaroxabanApixabanEdoxaban

Dabigatran

Targets of Oral Anticoagulants

CommonPathway

IX

VIII

Xa

Thrombin

Fibrin

ThrombinActivity

Contact

PropagationPhase

PlateletSurface

Fibrinogen

ApixabanRivaroxaban

Edoxaban

Dabigatran etexilate

Warfarin

InitiationPhase

TF VIIa

Warfarin vs. NOACs

Feature Warfarin New OralsOnset Slow Rapid

Dosing Variable Fixed

Food effect Yes No

Interactions Many Few

Monitoring Yes No

Offset Long Short

Landmark NOAC trials for AFib

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

RE-LY(Dabigatran)

2009

6 Trials of Warfarin vs Placebo1989 -1993

RE-LY: Dabigatran vs. Warfarin Study Design

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

RE-LY: Dabigatran vs. Warfarin Primary Efficacy Endpoint (CVA + Non-CNS Embolism)

0.01

0.02

0.03

0.05

0.04

Year0 0.5 1.0 1.5 2.0 2.5

0.0

Cum

ulat

ive

Haz

ard

Rat

es

110 mg: RR 0.91 (95% CI: 0.74-1.11)P < .001 (noninferiority); P = .34 (superiority)

150mg: RR 0.66 (95% CI: 0.53-0.82)P < .001 (superiority)


34%RRRWarfarin

Dabigatran 110 mgDabigatran 150 mg 1.11%

1.69%1.53%

RE-LY: Dabigatran vs. Warfarin Safety (Intracranial Hemorrhage)


*Dabigatran 110-mg dose associated with a 20% RRR in major hemorrhage compared with warfarin.

More GI bleeds with 150-mg dose compared with warfarin.

Rate RR P*Dabigatran110 mg BID 2.71% 0.80 .003 (sup)

Dabigatran150 mg BID 3.11% 0.93 .31 (sup)

Warfarin 3.36%

No reduction

20%



RE-LY(Dabigatran)

2009

ROCKET AF (Rivaroxaban)

2010


ROCKET AF: Rivaroxaban vs. Warfarin Study Design

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

Rivaroxaban Event Rate

Warfarin Event Rate

HR(95% CI)

PValue

On TreatmentN = 14,143

1.70 2.150.79

(0.65-0.95).015

ITTN = 14,171

2.12 2.420.88

(0.74-1.03).117

Rivaroxabanbetter

Warfarinbetter

Event Rates are per 100 patient-yearsBased on Safety on Treatment or Intention-to-Treat thru Site Notification populations

1.0 2.00.5


ROCKET AF: Rivaroxaban vs. Warfarin Primary Efficacy Endpoint (CVA + Non-CNS Embolism)

12% RRR

ROCKET AF: Rivaroxaban vs. Warfarin Safety (Major/Intracranial Bleed)


Rivaroxaban Warfarin

Event Rate or N (Rate)

Event Rate or N (Rate)

HR (95% CI)

PValue

Major 3.60 3.45 1.04 (0.90, 1.20) .576>2 g/dL Hgb drop 2.77 2.26 1.22 (1.03, 1.44) .019Transfusion (> 2 units) 1.65 1.32 1.25 (1.01, 1.55) .044Critical organ bleeding 0.82 1.18 0.69 (0.53, 0.91) .007

Bleeding causing death 0.24 0.48 0.50 (0.31, 0.79) .003Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) .019

Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02) .060

Intraventricular 2 (0.02) 4 (0.04)

Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00) .051

Subarachnoid 4 (0.04) 1 (0.01)

Event Rates are per 100 patient-years Based on Safety on Treatment Population

33% RRR

No difference



RE-LY(Dabigatran)

2009


2010

ARISTOTLE (Apixaban)

2011


ARISTOTLE: Apixaban vs WarfarinStudy Design

Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per yearHR 0.79 (95% CI, 0.66–0.95); P (superiority) = .011

No. at RiskApixaban 9120 8726 8440 6051 3464 1754Warfarin 9081 8620 8301 5972 3405 1768

Granger CB, et al. N Engl J Med. 2011;365:981-992

Warfarin

Apixaban

m

ARISTOTLE: Apixaban vs WarfarinPrimary Efficacy Endpoint (CVA + Non-CNS Embolism)

3024181260

4

3

2

1

0

Eve

nt, %

21% RRR

ARISTOTLE: Apixaban vs WarfarinBleeding Events

Granger CB, et al. N Engl J Med. 2011;365:981-992

Outcome

Apixaban(N = 9088)

Warfarin(N = 9052) HR

(95% CI)P

ValueEvent Rate, %/y Event Rate, %/y

Primary safety outcome: ISTH major bleeding* 2.13 3.09 0.69

(0.60-0.80) < .001

Intracranial 0.33 0.80 0.42 (0.30-0.58) < .001

Gastrointestinal 0.76 0.86 0.89 (0.70-1.15) .37

Major or clinically relevant non-major bleeding

4.07 6.01 0.68 (0.61-0.75) < .001

GUSTO severe bleeding 0.52 1.13 0.46 (0.35-0.60) < .001

TIMI major bleeding 0.96 1.69 0.57 (0.46-0.70) < .001

Any bleeding 18.1 25.8 0.71 (0.68-0.75) < .001

31% RRR

58% RRR



RE-LY(Dabigatran)

2009


2010


2011

ENGAGE AF-TIMI 48(Edoxaban)

2013


ENGAGE-AF TIMI 48: Edoxaban vs. WarfarinStudy Design

Giugliano RP, et al. N Engl J Med. 2013; 369:2093-2104.[17]

ENGAGE-AF TIMI 48: Edoxaban vs. WarfarinPrimary Efficacy Endpoint: Stroke/SEE

Hazard ratio (97.5% CI)

1.13

0.87

0.50 1.00 2.0

edoxaban superior edoxaban inferior

Treatment N nIncidence,

%/yr HR (97.5% CI)P for

superiorityWarfarin (median TTR 68.4%)

7036 337 1.80 - -

Edoxaban 60* mg QD 7035 296 1.57 0.87 (0.73–1.04) 0.08

Edoxaban 30* mg QD 7034 383 2.04 1.13 (0.96–1.34) 0.10

Giugliano RP, et al. N Engl J Med. 2013; 369:2093-2104

Edoxaban 60* mg QDvs warfarin

Edoxaban 30* mg QDvs warfarin

Warfarin TTR 68.4%

*Dose reduced by 50% in selected pts

P Values for Superiority

P = .08

P = .10

2.8 year median follow-up

13% RRR

ENGAGE-AF TIMI 48: Edoxaban vs. WarfarinMajor Bleeding

Giugliano RP, et al. N Engl J Med. 2013; 369:2093-2104.

Warfarin (Median TTR = 68.4%)Edoxaban 60 mg (HR = 0.80, 0.71–0.91)Edoxaban 30 mg (HR = 0.47, 0.41–0.55)

12

10

8

6

4

2

0

Maj

or b

leed

ing,

%

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Number at riskWarfarin 7012 6166 5630 5278 4941 3446 1687 970Edox (60) 7012 6039 5594 5232 4910 3471 1706 945Edox (30) 7002 6218 5791 5437 5110 3635 1793 986

y

TTR=time in therapeutic range; HR=hazard ratio.

20%

53%

a. Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151b. Patel MR, et al. N Engl J Med. 2011;365:883-891

c. Granger CB, et al. N Engl J Med. 2011;365:981-992d. Giugliano RP, et al. N Engl J Med. 2013;369:2093-2104


RE-LY(Dabigatran)

2009


2010


2011

ENGAGE AF-TIMI 48(Edoxaban)

2013

Warfarin vs Placebo2,900 Patients

NOACs vs warfarin71,683 Patients

vs

vs

vs

RE-LY ROCKET AF ARISTOTLE ENGAGE AFSample size 18,113 14,266 18,201 21,105

Study drug/dosedabigatran

110 mg 150 mg

rivaroxaban 20 mg

apixaban 5 mg

edoxaban60 mg 30 mg

Frequency Twice Daily Once Daily Twice Daily Once Daily

Design NoninferiorityPROBE

NoninferiorityDouble-blind



Median Follow-Up, years 2.0 1.9 1.8 2.8

Mean CHADS2 score 2.1 3.5 2.1 2.8

VKA naïve, % 50 38 43 41

TTR, %* 64 55 66 68

Stroke/SE (%/yr) vs warfarin 1.11 vs 1.69 1.7 vs 2.2 1.27 vs 1.60 1.57 vs 1.80

Major Bleed (%/yr) vs warfarin 3.1 vs 3.4 3.6 vs 3.4 4.07 vs 6.01 2.75 vs 3.43

* Percent time spent in therapeutic INR range 2-3

vs

vs

vs

✚

✚

✚

Meta-analysis of 4 Major NOAC Trials: Stroke or SE

ENGAGE AF-TIMI 48

ARISTOTLE

ROCKET AF

RE-LY

Combined

Favors NOAC Favors Warfarin

0.88 (0.75 - 1.02)

0.80 (0.67 - 0.95)

0.88 (0.75 - 1.03)

0.66 (0.53 - 0.82)

0.81 (0.73 - 0.91)

Risk Ratio (95% CI)

P < .0001

0.5 1 2

[Random Effects Model]

N = 58,541

Heterogeneity P = .13

[60 mg]

[150 mg]

19% RRR

Ruff CT, et al. Lancet. 2013

All-Cause Mortality

MI

Hemorrhagic Stroke

Ischemic Stroke

0.90 (0.85 - 0.95)

0.97 (0.78 - 1.20)

0.49 (0.38 - 0.64)

0.92 (0.83 - 1.02)

Risk Ratio (95% CI)

P = .0003

P = .77

P < .0001

P = .10


0.2 0.5 1 2

Heterogeneity P = NS for all outcomes

Meta-analysis of 4 Major NOAC Trials: Secondary Efficacy Endpoints


51% RRR

10% RRR

8% RRR (NS)

ARISTOTLE

ROCKET AF

Combined


Risk Ratio (95% CI)

0.80 (0.71-0.90)

0.71 (0.61-0.81)

1.03 (0.90-1.18)

0.94 (0.82-1.07)

0.86 (0.73-1.00)

0.5 1 2[Random Effects Model]N = 58,498

P = .06


RE-LY[150 mg]

ENGAGE AF-TIMI 48[60 mg]

Meta-analysis of 4 Major NOAC Trials: Major Bleeding


14% RRR

GI Bleeding

ICH

1.25 (1.01 - 1.55)

0.48 (0.39 - 0.59)

Risk Ratio (95% CI)

P = .043

P < .0001


0.2 0.5 1 2

Heterogeneity ICH, P = .22GI Bleeding, P = .009 Ruff CT, et al. Lancet. 2013

Meta-analysis of 4 Major NOAC Trials: Secondary Safety Outcomes

Risk Ratio (95% CI)

P-Interaction

Age, y< 75> 75

0.85 (0.73-0.99)0.78 (0.68-0.88)

P = .38

GenderFemaleMale

0.78 (0.65-0.94)0.84 (0.75-0.94)

P = .52

DiabetesNoYes

0.83 (0.74-0.93)0.80 (0.69-0.93)

P = .73

Prior Stroke or TIANoYes

0.78 (0.66-0.91)0.86 (0.76-0.98)

P = .30

CrCl< 5050-80> 80

0.79 (0.65-0.96)0.75 (0.66-0.85)0.98 (0.79-1.22)

P = .12

CHADS2 Score0-12

3-6

0.75 (0.54-1.04)0.86 (0.70-1.05)0.80 (0.72-0.89)

P = .76

VKA StatusNaïve

Experienced0.75 (0.66-0.86)0.85 (0.70-1.03)

P =.31

Center-Based TTR< 66%> 66%

0.77 (0.65-0.92)0.82 (0.71-0.95)

P = .60

Favors NOAC Favors Warfarin0.5 1 2

Meta-analysis of 4 Major NOAC Trials: Subgroups: Stroke/SEE

Risk Ratio (95% CI) P-Interaction

Age< 75> 75

0.79 (0.67-0.94)0.93 (0.74-1.17)

P = .28

GenderFemaleMale

0.75 (0.58-0.97)0.90 (0.72-1.12)

P = .29

DiabetesNoYes

0.71 (0.54-0.93)0.90 (0.78-1.04)

P = .12

Prior Stroke or TIANoYes

0.85 (0.72-1.01)0.89 (0.77-1.02)

P = .70

CrCl< 5050-80> 80

0.74 (0.52-1.05)0.91 (0.76-1.08)0.85 (0.66-1.10)

P = .57

CHADS2 Score0-12

3-6

0.60 (0.45-0.80)0.88 (0.65-1.20)0.86 (0.71-1.04)

P = .09

VKA StatusNaïve

Experienced0.84 (0.76-0.93)0.87 (0.70-1.08)

P =.78

Center-Based TTR< 66%> 66%

0.69 (0.59-0.81)0.93 (0.76-1.13)

P = .022

Favors NOAC0.2 0.5 1 2

Favors Warfarin

Meta-analysis of 4 Major NOAC Trials: Subgroups: Bleeding

Summary of NOAC trials

• NOACs significantly reduce stroke (19%)

– Primarily driven by reduction in hemorrhagic stroke (51%)

• NOACs significantly reduce mortality (10%)

• Trend toward less bleeding

– Substantial reduction in ICH (52%)

– Increased GI bleeding (25%)

• The relative efficacy and safety of NOACs is consistent across a wide spectrum of AF patients

Practical Considerations for Choosing a NOAC

Initiating therapy with NOAC

1. Is a NOAC indicated?

2. Consider comorbid medical conditions

3. Consider potential drug-drug interactions

4. Other factors that may warrant dose reduction?

5. Educate on importance of compliance

< 65 years and lone AF (including females)

Assess risk of stroke(CHA2DS2-VASc score)

Oral anticoagulant therapy

Assess bleeding risk(HAS-BLED score)

Consider patient valuesand preferences

NOAC VKA

No antithrombotic therapy

0 1 > 2

Yes

No

Camm AJ, et al. Europace. 2012;14:1385-1413

2012 ESC Guidelines Recommendations for OAC in AF

2014 AHA/ACC/HRS Guidelines Recommendations for OAC in AF

< 65 years and lone AF (including females)

Assess risk of stroke(CHA2DS2-VASc score)

Oral anticoagulant therapy

Assess bleeding risk(HAS-BLED score)

Consider patient valuesand preferences

NOAC VKA

No antithrombotic therapy

0 1 > 2

Yes

No

Camm AJ, et al. Europace. 2012;14:1385-1413

2012 ESC Guidelines Recommendations for OAC in AF







Preferred NOAC by Clinical ScenarioHistory of GI Bleed Consider agent with lowest GI bleed Apixaban

Preferred OAC by Clinical ScenarioHistory of GI bleeding


High risk of stroke; low bleeding risk

Consider agent with best efficacy in reducing ischemic stroke Dabigatran

ENGAGE AF-TIMI 48

ARISTOTLE

ROCKET AF

RE-LY

Combined


0.88 (0.75 - 1.02)

0.80 (0.67 - 0.95)

0.88 (0.75 - 1.03)

0.66 (0.53 - 0.82)

0.81 (0.73 - 0.91)

Risk Ratio (95% CI)

P < .0001

0.5 1 2

[Random Effects Model]

N = 58,541


[60 mg]

[150 mg]

Ischemic Stroke/SE




High risk of bleeding (e.g. HAS-BLED ≥ 3)

Consider agent/dose with lower rate of bleeding events

ApixabanEdoxaban

ARISTOTLE

ROCKET AF

Combined


Risk Ratio (95% CI)

0.80 (0.71-0.90)

0.71 (0.61-0.81)

1.03 (0.90-1.18)

0.94 (0.82-1.07)

0.86 (0.73-1.00)

0.5 1 2

P = .06

RE-LY[150 mg]

ENGAGE AF-TIMI 48[60 mg]

Major Bleeding






ApixabanEdoxaban

History of prior strokeConsider agent best studied in

secondary prevention population Rivaroxaban

NOAC Trials: Baseline CharacteristicsRE-LYa

(Dabigatran)ROCKET-AFb

(Rivaroxaban)ARISTOTLEc

(Apixaban)ENGAGE AFd

(Edoxaban)

# Randomized 18,113 14,264 18,201 21,105

Age, years 72 ± 9 73 [65-78] 70 [63-76] 72 [64-78]

Female, % 37 40 35 38

Paroxysmal AF, % 32 18 15 25

VKA naïve, % 50 38 43 41

CHADS2 score 2.1 3.5 2.1 2.8

32

35

33 13

874753

34

36

30

a. Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151.[14]

b. Patel MR, et al. N Engl J Med. 2011;365:883-891.[15]

c. Granger CB, et al. N Engl J Med. 2011;365:981-992.[16]

d. Giugliano RP, et al. N Engl J Med. 2013;369:2093-2104.[17]

CHADS2

23-6

0-1






ApixabanEdoxaban



Patient Preference; Compliance concerns

Consider agents that are dosed once daily

RivaroxabanEdoxaban

Moderate-to-severe CKD (CrCl > 15)

Consider agent with established dosing in this population

Apixaban 2.5Rivaroxaban 15

Edoxaban 30

Preferred NOAC by Clinical Scenario Chronic Kidney Disease

Qamar A, Bhatt, D. L. Nat. Rev. Nephrol. 2015






ApixabanEdoxaban



Patient Preference; Compliance concerns

Consider agents that are dosed once daily

RivaroxabanEdoxaban

Moderate-to-severe CKD (CrCl > 15)

Consider agent with established dosing in this population

Apixaban 2.5Rivaroxaban 15

Edoxaban 30

Advanced CKD (CrCl < 15)

Consider that NOACs are not well studied in such patients Warfarin







NOAC drug-drug InteractionsTransporter CYP Metabolism

Rivaroxaban P-gp Yes

Apixaban P-gp Yes

Edoxaban P-gp Minimal

Dabigatran P-gp None

Heidbuchel H, et al. Eur Heart J. 2013;34:2094-2106

via Dabigatran Apixaban Edoxaban Rivaroxaban

VerapamilP-gp weak

CYP3A4

+12-180%reduce dose

take togetherno data +53% (SR)

reduce dose

minor effectuse with caution

if CrCl: 15-50ml/min

DiltiazemP-gp weak

CYP3A4no effect +40% no data

minor effectuse with caution

if CrCl: 15-50ml/min

Amiodarone P-gp +12-60% no data no effectminor effect

use with cautionif CrCl: 15-50ml/min

DronedaroneP-gp weak

CYP3A4+70-100% no data

+88% reduce dose by

50%No data yet

Conazole antifungals

P-gp and CYP3A4 inhibition

+150% +100% No Data +160%

Not recommended/contraindicated

Reduce dose

Reduce dose if 2 factors or more

No data yet

Important Drug-Drug Interactions








via Dabigatran Apixaban Edoxaban Rivaroxaban

Aged ≥ 80 years Increased plasma level

Aged ≥ 75 years Increased plasma level

Weight ≤ 60 kg Increased plasma level

Renal function Increased plasma level

Not recommended/contraindicated

Reduce dose

Reduce dose if 2 factors or more

No data yet

Important Drug-Drug Interactions

Other Factors that Increase Bleeding Risk • Pharmacodynamic interactions

(Antiplatelet drugs, NSAIDS, Systemic steroid therapy, Other anticoagulants)

• Thrombocytopenia (e.g. chemotherapy)• HAS-BLED ≥ 3







Use of concurrent antiplatelet therapy?

• Use of ASA and/or clopidogrel is common in patients with AF

• ASA substantially increases bleeding risk in combination with OAC therapy

ASA use in NOAC Trials




• Additional ischemic protection with concurrent ASA use is minimal outside of recent ACS

WARIS-2: Secondary Prevention after MI

Warfarin improves event-free survival post-MI relative to ASA




• Additional ischemic protection with concurrent ASA use is minimal outside of recent ACS

• In patients with stable PAD/CAD, strongly consider discontinuation of ASA to mitigate long-term bleeding

What is the role of warfarin given given the availability of NOACs?

What is the role of warfarin given given the availability of NOACs?

• Prosthetic heart valve in situ

• Presence of hypertrophic cardiomyopathy

• Expectation of patient poor adherence

• Significant renal impairment is present

• The patient has recent stent or warranting antiplatelet therapy for other reasons

• Cost is prohibitive

Closing Thoughts• The prevalence of AF and its associated morbidity is growing

providing physicians with opportunities to provide stroke-prevention strategies in patients at high risk.

• Warfarin has an established efficacy in reducing stroke in patients with AF but its use is limited by dosing complexity and bleeding hazards.

• NOACs provide a more convenient alternative to warfarin with fixed dosing and no need for drug monitoring.

• ASA is inadequate to reduce risk of stroke in patients with a CHADS-VASc of ≥ 2.

Closing Thoughts• As a class, NOACs have demonstrated comparable efficacy

to warfarin reducing ischemic stroke and superiority in reducing total/hemorrhagic stroke, driven largely by a 50% reduction in intracranial hemorrhage.

• NOACS have important differences in pharmacology (e.g. renal elimination) that impact dosing strategies and may alter the risk-benefit ratio.

• Use of NOACs does not replace the need for close follow-up

• Ongoing studies will help us determine the role of treating more complex patients with NOACs and assessing outcomes in “real world” patients.

Questions?

ROCKET AF: Rivaroxaban vs. Warfarin Primary Efficacy Endpoint (CVA + Non-CNS Embolism)


0

1

2

3

4

5

6

0 120 240 360 480 600 720 840 960No. at risk:Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655

Warfarin

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

P-value Non-Inferiority: <0.001

Days from Randomization

Cum

ulat

ive

even

t ra

te (

%)

Rivaroxaban

R

Event Rate

P-gp = P-glycoprotein

Characteristic Rivaroxaban Apixaban Edoxaban Dabigatran

Target Factor Xa Factor Xa Factor Xa Thrombin

Prodrug No No No Yes

Bioavailability, % 80 60 62 6

Dosing QD BID QD BID

Half life, h 7-11 12 9-11 12-17

Renal, % 33 (66) 25 50 80

Monitoring No No No No

Interactions 3A4/P-gp 3A4/P-gp P-gp P-gp


Pharmacokinetics of NOACs

Pharmacokinetics of NOACs: Absorption & Metabolism

Limitations of NOACs

1. Antidotes not universally available2. Lack of standard measurement to promote

adherence3. Lack of compelling evidence that they are

superior to patients well controlled with warfarin

4. Tolerability: GI bleeding, Renal dysfunction5. High cost

Management of Bleeding

Follow-up for NOAC patientsInterval Comments

Compliance Each visitInspect remaining medicationStress importance of complianceInform about compliance aids

Thrombo-embolism Each visit Cerebral, systemic and pulmonary circulation

Bleeding Each visit“Nuisance” bleeding – prevention possible?Bleeding with risk or impact on QoL – prevention possible? Need to revise dose?

Side effects Each visitContinuation? Temporary cessation with bridging? Change of anticoagulant drug?

Co-medications Each visitPrescription or over-the counter drugs?Even temporary use can be risky

Blood sampling

Yearly6-monthly

3-monthlyon indication

Hemoglobin, renal, liver functionRenal function if CrCl 30-60 ml/min or if on dabigatran and aged >75 years or fragile

If CrCl 15-30 ml/minIf intercurring condition may impact renal or hepatic function.

Dealing with Dosing Errors

Missed dose: BID: take missed dose up to 6 h after scheduled

intake. If not possible skip dose and take next

scheduled dose.

QD: take missed dose up to 12 h after scheduled

intake. If not possible skip dose and take next

scheduled dose.

Double dose: BID: skip next planned dose and restart BID after 24 h.

QD: continue normal regimen.

Uncertainty about

intake:

BID: continue normal regimen.

QD: take another dose then continue normal regimen.

Overdose: Hospitalization advised.

ENGAGE-AF TIMI 48: Edoxaban vs. WarfarinMajor Bleeding

Giugliano RP, et al. N Engl J Med. 2013; 369:2093-2104.TTR=time in therapeutic range; HR=hazard ratio.

OutcomeWarfarin(n = 7012)

Edox60 mg

(n = 7012)

Edoxaban 60 mg

vs Warfarin

Edoxaban30 mg

(n = 7002)

Edoxaban 30 mg

vs Warfarin

%/y %/y HR P %/y HR P

Major bleeding 3.43 2.75 0.80 < .001 1.61 0.47 < .001

Life-threatening bleeding 0.78 0.40 0.51 < .001 0.25 0.32 < .001

CRNM bleeding 10.15 8.67 0.86 < .001 6.60 0.66 < .001

Minor bleeding 4.89 4.12 0.84 . 002 3.52 0.72 < .001

Major or CRNM bleeding 13.02 11.10 0.86 < .001 7.97 0.62 < .001

Any overt bleeding 16.40 14.15 0.87 < .001 10.68 0.66 < .001

Preferred NOAC by Clinical Scenario Chronic Kidney Disease


AF is rare in individuals < 40 years of age but the prevalence doubles every decade after age 55

Age, years

Prev

alen

ce, p

erce

nt

Go AS, et al. JAMA. 2001; 285:2370-2375.

0

2

4

6

8

10

12

<55 55-59 60-64 65-69 70-74 75-79 80-84 >85

Women Men

BAFTA TrialWarfarin superior to ASA in patients with AF

NOAC dosing: BID vs. QD

Rivaroxabanb

Peak to Trough Ratio ~18Apixabana

Peak to Trough Ratio ~3

Rivaroxaban 10 mg QDSteady State Concentration, ng/mL

Apixaban 2.5 mg BIDSteady State Concentration, ng/mL

Time, h0 6 12 18 24

Stea

dy S

tate

Con

cent

rati

on,

ng/m

L

0

20

40

60

80

100

120

140

Time, h0 6 12 18 24

Stea

dy S

tate

Con

cent

rati

on,

ng/m

L

0

20

40

60

80

100

120

140Apixaban 2.5 mg BID Rivaroxaban 10 mg qd

Unique Properties of NOACs

Property SignificanceShort half-life Adherence critical

Renal excretionCareful patient selection; monitor creatinine clearance; adjust dose if necessary

Drug-drug interactions Drug-specific

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