A New Era in Anticoagulation Management - PowerPoint Presentation

Slide1

A New Era in Anticoagulation Management

Allyson Sarigianis, Pharm.D.

October 19, 2013Slide2

Objectives

Review current practice recommendations for prevention of stroke/systemic embolism in atrial fibrillation

Compare and contrast pharmacology between warfarin and target specific oral anticoagulants (TSOACs)

Summarize the efficacy and safety of TSOACs for atrial fibrillation

Examine the differences between warfarin and TSOACs for atrial fibrillation

Identify future clinical implication for new era in anticoagulation management based on AT9 2012 Chest GuidelinesSlide3

Current

FDA Approved Indications

Warfarin

Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE)

Prophylaxis and treatment of thromboembolic

complications

associated with atrial fibrillation and/or cardiac valve replacement

Reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events

Dabigatran

Stroke prevention in patients with non-valvular

atrial fibrillation

Rivaroxaban

Stroke prevention in patients with non-valvular atrial fibrillation

Prevention of VTE in patients undergoing hip or knee replacement

Acute treatment of DVT/PE

Secondary prevention

of DVT/PE

Apixaban

Stroke prevention in patients with non-valvular atrial fibrillationSlide4
Slide5

WarfarinSlide6

Warfarin

Kinetics

Absorption

Oral: Rapid, complete

Distribution

0.14 L/kg

Metabolism

Hepatic, primarily via CYP2C9; minor pathways include CYP2C8, 2C18, 2C19, 1A2, and 3A4

Excretion

Urine (92%, primarily as metabolites)

Half-life

20-60 hoursSlide7

Warfarin

Onset of action:

5-7 days

May requiring bridging

Antidote:

Vitamin K, FFP, PRBC

Interactions:

Foods with high vitamin K contentSlide8

Warfarin

Medications

Amiodarone

Antiplatelets

Azole

antifungals

(

fluconazole

)2nd

/3

rd-

gen

Cephalosporins

Fluoroquinolones

(ciprofloxacin)

Griseofulvin

Isoniazid

Macrolides

(

clarithromycin

)

Metronidazole

NSAIDs

Penicillins

(

nafcillin

)

Prednisone

Rifampin

SSRIs

Sulfonamides (

Bactrim

)

Tetracyclines

(

Doxycycline

)

Herbals

Ginger

Gingko

Fenugreek

Chamomile

St. John’s

Wort

Slide9

Warfarin

ADRs

Bleeding/Hemorrhage/Hematuria

Vasculitis

Dermatitis,

pruritus,

urticaria

Abdominal

pain

, N/V/D

Anemia

Skin necrosis, gangrene, “purple toes” syndromeSlide10

Dabigatran (Pradaxa)Slide11

Dabigatran

MOA: direct thrombin inhibitor which inhibits:

Both free and fibrin-bound thrombin

Cleavage of fibrinogen to fibrin

Activation of factors V, VIII, XI, and XIII

Thrombin-induced platelet aggregationSlide12

Dabigatran

Kinetics

Absorption

Rapid; initially slow postoperatively

Distribution

V

d

: 50-70 L

Metabolism

Hepatic; rapidly and completely hydrolyzed to active form by plasma and hepatic

esterases

Excretion

Renal (80%)

Half-life

12-17 hoursSlide13

Dabigatran

Monitoring

PPT

Onset: 1 hour, delayed by food

Antidote: None

ADRs

Bleeding (8% to 33%; major ≤ 6%)

Dyspepsia (11%)Slide14

Dabigatran

Contraindications

Hypersensitivity to dabigatran or any component

Active bleeding

Warnings/Precautions

Bleeding

Renal impairment

Anticoagulants

Invasive/surgical invasions

P-

gp

inducers/inhibitorsSlide15

Dabigatran

Drug interactions

Category X

: P-Gp inducers

Category D

: Amiodarone, P-Gp inhibitors, quinidine, St. john’s

Wort

, verapamil

Category C

: antacids, anticoagulants,

antiplatelet

agents, atorvastatin, dasantinib, ibritumonmab

, NSAIDs,

prostacyclin

analogs, PPIs, salicylates, thrombolytic agents Slide16

Dabigatran

FDA Bleeding Risk:

[12-7-2011]

Evaluating post-marketing reports of serious bleeding

“Bleeding that may lead to serious or even fatal outcomes is a well-recognized complication of all anticoagulant therapies.” Slide17

Dabigatran

ISMP Medication Safety Alert: Quarter Watch

[01-12-12]

932 serious adverse events for 1

st

quarter of 2011

120 deaths

25 cases of permanent disability

543 cases requiring hospitalization

505 cases involved hemorrhage:

elderly patients (Median age of 80)

120 cases of hemorrhagic stroke Slide18

Dabigatran

FDA

Drug Safety Communication:

[

11‐02‐2012

]

“…

FDA investigated the actual rates of gastrointestinal bleeding

and

intracranial hemorrhage

for

new users of [dabigatran] compared to new users of warfarin. The results of this Mini‐Sentinel assessment indicate that bleeding rates associated with new use of [dabigatran] do not appear to be higher than bleeding rates associated with new use of

warfarin

….”

18Slide19

Dabigatran

FDA Drug Safety

Communication: [

12-19-2012

]

“A

clinical trial in Europe (the RE-ALIGN trial

)

was recently stopped because

[dabigatran] users

were more likely to experience strokes, heart attacks, and blood clots forming on the mechanical heart valves than were users of the anticoagulant warfarin.

There was also more bleeding after valve surgery in the

[dabigatran] users

than in the warfarin

users [dabigatran]

is not approved for patients with

AF caused

by heart valve problems.

“

19Slide20

Dabigatran

May be appropriate

MAY NOT

be appropriate

NOT appropriate

Ability to comply with twice daily drug

regimen

History of non-adherence

Severe renal impairment

(CrCl <30 ml/min)

Unstable INRs on warfarin (unrelated to adherence)

Stable INRs on warfarin

History of GI bleeding or recent ulcers

Difficulty obtaining regular INRs on warfarin

Advanced age (75-80 yrs and older; consider benefits and risks)

Active liver disease

Complicated interacting drug regimens on warfarin

Pregnancy, at risk of pregnancy, or lactating

High risk of intracranial bleed

Need for concomitant treatment with P-

gp

inducer (

e.g

,. rifampin, St. John’s

Wort

)

Medication regimen does not include drugs that interact with dabigatran

Moderate renal impairment (CrCl 30-50 ml/min) and the need for concomitant treatment with the P-

gp

inhibitors

dronedarone

or systemic

ketoconazole

Good renal function

No history of GI bleeding or recent ulcersSlide21

Rivaroxaban (Xarelto

)Slide22

Rivaroxaban

MOA: selective/reversible direct inhibitor of factor

Xa

Prevents the conversion of prothrombin to thrombin

Thrombin both activates platelets and catalyzes the conversion of fibrinogen to fibrinSlide23

Rivaroxaban

Creatine

Clearance (mL/min)

>50

50-30

29-15

<15 or HD

Atrial

fibrillation

20 mg po daily

15 mg po daily

Avoid use

Postoperative

thromboprophylaxis

10 mg

po daily

Knee:

12-14 days

Hip:

35 days

10 mg po daily,

use with caution

Avoid use

Avoid use

Treatment of PE/VTE

15 mg twice daily x21 days, then 20 mg po daily

Use

with caution

Avoid

use

Avoid use

Secondary

Prophaxis

for PE/VTE

20 mg po

daily

Use

with caution

Avoid

use

Avoid

useSlide24

Rivaroxaban

Kinetics

Absorption

Rapid

Distribution

V

dss

: ~50 L

Metabolism

Hepatic (33%) via CYP3A4/5 and CYP2J2

Excretion

Renal

(66% primarily via active tubular secretion); feces (28%)

Half-life

5-9 hours Slide25

Rivaroxaban

Monitoring

Prothrombin

time (PT)

CBC with differential

Renal/hepatic function

Onset:

2-4

hours

Antidote: NoneSlide26

Rivaroxaban

ADRs

Pruritus (2%)

Bleeding

DVT prophylaxis: 6% [major: <1%]

Atrial fibrillation: 21% [major: 6%]

Thrombocytopenia (3%)

Increase in liver enzymes (7%-3%)Slide27

Rivaroxaban

Contraindications

Hypersensitivity to rivaroxaban or any component

Active bleeding

Drug Interactions

Category X

: P-

Gp

or 3A4 inhibitors/inducers

Category C

: anticoagulants, antiplatelet agents, NSAIDs,

salicylatesSlide28

Rivaroxaban

ISMP Medication Safety

Alert: 10/4/2012

Primary event: Thrombus

158 cases, 44.4% of the total

Hemorrhage

121

cases, 34% of the

totalSlide29

Apixaban (Eliquis)Slide30

Apixaban

MOA: oral direct

Xa

inhibitor

Dose

: 5mg twice daily

Dose reduction to 2.5mg twice daily if 2+ of the following:

Age ≥80 years

Body weight ≤60kg

Scr ≥1.5mg/dl

AVOID in CrCl <15 ml/minSlide31

Apixaban

Kinetics

Absorption

Rapid; Intestines

Distribution

V

d

: 21 L

Metabolism

15% liver metabolism

CYP3A4/5

P-

gp

Excretion

Primarily Biliary/Fecal (46-56%)

Renal (27%)

unchanged

Half-life

8 to 15 hours Slide32

Apixaban

Monitoring

Minimal impact on the PT, INR, or

aPTT

Factor

Xa

inhibition

Onset:

3-4 hours

Antidote: NoneSlide33

Clinical EvidenceSlide34

RE-LY

ROCKET-AF

ARISTOTLE

Dabigatran

150mg BID

vs. warfarin

Rivaroxaban

20mg daily

vs. warfarin

Apixaban5mg BID

vs. warfarin

Study Design

Trial design

RCT Open blinded assessment

RCT DB DD

RCT DB DD

Sample size

(n)

18,000+

14,000+

18,000+

Inclusion criteria

AF and selected risk factor(s) for

embolization

AF and CHADS2 ≥2

AF or flutter and CHADS2 ≥1

Key exclusion criteria

Valvular AF

Use of ASA ≥100 mg/day

CrCl <30 ml/min

Valvular AF;

Use of ASA >100 mg/day

CrCl <30 ml/min

Valvular AF

Need for ASA >165 mg/day

SCr >

2.5mg/

dL

or CrCl <

25ml/min

Follow-up

(mean)

2 yr

1.9

yr

1.8 yr

Outcome Definitions

Primary

Efficacy

Composite of systemic

embolism

and

stroke

(ischemic

or hemorrhagic)

Major Bleeding

ISTH: fatal

/

critical organ bleed;

decrease

≥

2g/dL Hbg or transfusion of ≥2U blood

Mortality

All causes

Baseline Characteristics

Age

(years)

71 (mean)

73 (median)

70 (median)

Female

(%)

36.4%

39.7%

35.2 %

CHADS2

(mean)

2.1

3.5

2.1

Previous embolic

episode

(%)

20%

(stroke or TIA only)

55%

(

stroke,TIA

,

systemic

embolism

)

19%

(stroke, TIA,

systemic

embolism

)

TTR

(%)

(Standard 60-65%)

64%

55%

62%Slide35

Comparison of Efficacy Results

RE-LY

ROCKETAF

ARISTOTLE

Outcome (%/year

)

Dabigatran

150mg BID

vs

.

warfarin

p Value

Rivaroxaban 20mg daily

vs.

warfarin

p Value

Apixaban 5mg BID

vs.

warfarin

p Value

Primary Outcome

Stroke or systemic embolism

1.1 vs. 1.7%

p<0.001 NNT 88

2.1 vs. 2.4%

p=0.12

1.3 vs. 1.6%

p=0.01

NNT 167

Stroke

1.0 vs. 1.6%

p<0.001

NNT 88

1.65 vs. 1.96%

p=0.09

1.2 vs. 1.5%

p=0.01

NNT 175

Ischemic stroke

0.9 vs. 1.3%

p=0.03

NNT 132

1.3 vs. 1.4

p=0.58

0.97 vs. 1.05%

p=0.42

Hemorrhagic stroke

0.1vs0.4%

p<0.001

NNT 182

0.26 vs. 0.44%

p=0.02

NNT 333

0.24 vs. 0.47%

p<0.001

NNT 238

All cause death

3.6 vs. 4.1%

p=0.051

4.5 vs. 4.9%

p=0.15

3.5 vs. 3.9

p=0.047

NNT 132

MI/ACS

0.7 vs. 0.5%

p=0.048

NNH 239

0.9 vs. 1.1%

p=0.12

0.5 vs. 0.6%

p=0.37Slide36

Comparison of Safety Results

RE-LY

ROCKETAF

ARISTOTLE

Major bleed

3.1 vs. 3.36%

p=0.31

3.6 vs. 3.4%

p=0.58

2.1 vs. 3.1%

p<0.001

NNT 67

Intracranial bleed

0.3 vs. 0.74%

p<0.001

NNT 116

0.5 vs. 0.7%

p=0.02

NNT 250

0.3 vs. 0.8%

p<0.001

NNT 128

GI bleed

1.5 vs. 1.0%

p<0.001

NNH 100

3.2 vs. 2.2%**

p=0.001

NNH 100

0.76 vs. 0.86%

0.37Slide37

GuidelinesSlide38

ACC/AHA/HRS 2011

F

ocused

update recommendation:

Dabigatran is a useful alternative to warfarin for the prevention of stroke and systemic embolism in patients with paroxysmal to permanent AF and risk factors for stroke and systemic embolism

Do

not have a prosthetic heart valve,

hemodynamically

significant valve disease, severe renal failure (CrCl < 15mL/min), or impaired liver

disease

Alternative to warfarin for moderate-high risk patients:

Difficulty achieving therapeutic INRs

Inability obtaining regular

bloodwork

monitoring

Low risk for GI bleeding

Low risk for cardiovascular eventsSlide39

AT9 2012 Chest

2.1.8

CHADS =

0

No therapy rather than antithrombotic therapy

(Grade 2B)

2.1.9

CHADS =

1

Oral

anticoagulation rather than no

therapy (Grade 1B) Slide40

AT9 2012 Chest

2.1.10

CHADS =2+

Oral anticoagulation rather than no therapy

(Grade 1A)

2.1.11

Dabigatran

150 mg twice daily

rather than

adjusted-dose VKA therapy (target

INR range

, 2.0-3.0) (Grade 2B) Slide41

The FutureSlide42
Slide43

ConclusionsSlide44

Comparison of agents

Dabigatran

Rivaroxaban

Apixaban

Target

Factor IIa

Factor Xa

Factor Xa

FDA Indications

Nonvalvular

AF

Nonvalvular

AF

Ortho VTE Proph

Acute

Treatment VTE

Nonvalvular

AF

Prodrug

Yes

No

No

Dosing

Twice daily

Daily, with food

Twice daily

Onset

1-2 hrs

2-4 hrs

3-4

hrs

Half-life (h)

14–17

7–11

8–14

Renal

Adjustment

↓ 15-29ml/min

Avoid < 15 ml/min

Avoid

< 30 ml/min

Avoid < 15 ml/min

Drug

Interactions

P-gp

CYP3A4/P-gp

CYP3A4/P-gpSlide45

Conclusions

Efficacy

superiority

vs

non- inferiority

ADRs

ACS / MI risk

Cost

Clinical guidelinesSlide46

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JI. New oral anticoagulants in development.

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