sotiris antoniou consultant pharmacist, cardiovascular ... · new oral anticoagulants sotiris...

New Oral Anticoagulants

Sotiris Antoniou

Consultant Pharmacist, Cardiovascular Medicine

Barts and the London NHS Trust &

North East London Cardiovascular & Stroke Network

Contents

� Warfarin - summary

� Concerns

� Time In Range (TIR)

� Newer anticoagulants – the evidence base!

� Dabigatran

� Rivaroxaban (not yet published)

� Apixaban

Narrow therapeutic range with VKA

Target INR

(2.0-3.0)

00

2020

4040

6060

8080

Eve

nts

/ 100

0 pa

tient

yea

rsE

vent

s / 1

000

patie

nt y

ears

Intracranial haemorrhage

Ischaemic stroke

<1.5<1.5 1.51.5––1.91.9 2.02.0––2.52.5 2.62.6––3.03.0 3.13.1––3.53.5 3.63.6--4.04.0 4.14.1--4.54.5 >4.5>4.5

The anticoagulant effect

of vitamin K antagonists

are optimized when

therapeutic doses are

maintained within a very

narrow range

Hylek EM, et al. Hylek EM, et al. N Eng J Med N Eng J Med 2003; 349:10192003; 349:1019--1026.1026.

Quality of warfarin controlInternational Normalized Ratio

Quality of warfarin controlInternational Normalized Ratio

0%

20%

40%

60%

80%

100%

3 6 9 12 15 18 21

<1.8

>3.2

2.0-3.0

Treatment duration (months)

Tim

e in

ran

ge (

%)

66% 81%

New anticoagulants

FibrinFibrinFibrinogenFibrinogenAdapted from Weitz & Bates,Adapted from Weitz & Bates, J Thromb Haemost J Thromb Haemost 20052005

TFPI (tifacogin)TFPI (tifacogin)

FondaparinuxFondaparinux

IdraparinuxIdraparinux

RivaroxabanRivaroxaban

ApixabanApixaban

LY517717LY517717

YM150YM150

DUDU--176b176b

PRTPRT--054021054021

XimelagatranXimelagatran

DabigatranDabigatran

ORALORAL PARENTERALPARENTERAL

DXDX--9065a9065a

OtamixabanOtamixaban

XaXa

IIaIIa

TF/VIIaTF/VIIa

XX IXIX

IXaIXaVIIIaVIIIa

VaVa

IIII

ATAT

APC (drotrecogin alfa)APC (drotrecogin alfa)

sTM (ARTsTM (ART--123)123)

TTP889TTP889

� 18,113 patients randomised during 2 years1,2

� 50% of enrolled patients were naïve to previous oral AC

� Median treatment duration: 2 years

� 951 centres in 44 countries

� Dec 2005 to March 2009

RE-LY®: Randomised Evaluation of

Long term anticoagulant therapy

1. Ezekowitz MD, et al. Am Heart J 2009;157:805-10.

2. Connolly SJ., et al. NEJM Aug 30th 2009.

RE-LY: Study Design

Atrial fibrillation

≥1 Risk Factor

Absence of contra-indications

951 centers in 44 countries

R

Warfarin

adjusted

(INR 2.0-3.0)

N=6000

Dabigatran

Etexilate

110 mg BID

N=6000

Dabigatran

Etexilate

150 mg BID

N=6000

Blinded Event Adjudication.

Open Blinded

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

RE-LY® – inclusion criteria

1) Documented atrial fibrillation and

2) One additional risk factor for stroke:

a) History of previous stroke, TIA, or systemic embolism

b) LVEF less than 40%

c) Symptomatic Heart Failure, NYHA Class II or greater

d) Age of 75 years or more

e) Age of 65 years or more and one of the following additional risk factors: Diabetes mellitus, CAD or Hypertension

RE-LY: Baseline Characteristics

Characteristic Dabigatran 110

mg

Dabigatran 150

mgWarfarin

Randomized 6015 6076 6022

Mean age (years) 71.4 71.5 71.6

Male (%) 64.3 63.2 63.3

CHADS2 score (mean)

0-1 (%)2 (%)

3+ (%)

2.1

32.634.7

32.7

2.2

32.235.2

32.6

2.1

30.937.0

32.1

Prior stroke/TIA (%) 19.9 20.3 19.8

Prior MI (%) 16.8 16.9 16.1

CHF (%) 32.2 31.8 31.9

Baseline ASA (%) 40.0 38.7 40.6

Warfarin Naïve (%) 49.9 49.8 51.4

Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151

Stroke or systemic embolism (SSE)

0.50 0.75 1.00 1.25 1.50

Dabigatran 110 mg

vs. warfarin

Dabigatran 150 mg

vs. warfarin

Noninferiorityp-value

<0.001

<0.001

Superiorityp-value

0.34

<0.001

Ma

rgin

= 1

.46

HR (95% CI)

Connolly SJ., et al. NEJM 2009.DOI 10.1056/NEJMoa0905561

0.01

0.02

0.03

0.05

0.04

Cu

mu

lati

ve

ha

zard

ra

tes

RR 0.91

(95% CI: 0.74–1.11)

p<0.001 (NI)

p=0.34 (Sup)

RR 0.66

(95% CI: 0.53–0.82)

p<0.001 (NI)

p<0.001 (Sup)

Years

0 0.5 1.0 1.5 2.0 2.5

0.0

Warfarin

Dabigatran etexilate 110 mg

Dabigatran etexilate 150 mg

RR, relative risk; CI, confidence interval; NI, non-inferior; Sup, superior

Time to first stroke / SSE

RRR

34%


NNT 172

RR 0.26 (95% CI: 0.14–0.49)

p<0.001 (sup)

Haemorrhagic stroke


RR 0.31 (95% CI: 0.17–0.56)

p<0.001 (sup)

Nu

mb

er

of

eve

nts

6,015 6,076 6,022

1412

45

0

10

20

30

40

50

D110 mg BID D150 mg BID Warfarin

0.10%

0.38%RRR

69%

RRR

74%

0.12%

NNT 385

3.75 3.64

4.13

0.00

1.00

2.00

3.00

4.00

D110 mg BID D150 mg BID Warfarin

RR 0.88 (95% CI: 0.77–1.00)

p=0.051 (sup)

All cause mortalityRR 0.91 (95% CI: 0.80–1.03)

p=0.13 (sup)

446 / 6,015 438 / 6,076 487 / 6,022

% p

er

ye

ar


Lancet, Sep 2010 - 376,975-83

Major bleeding and components

CharacteristicCharacteristicDD

110 mg110 mgDD

150 mg150 mgWarfarinWarfarin

PP--valuevalue

110 vs. W110 vs. WPP--valuevalue

150 vs. W150 vs. W

Number of patients (n) 6015 6076 6022

Major bleeding 2.71 3.11 3.36 0.003 0.31

- Life threatening

- Non-life threatening

- Gastrointestinal

1.22

1.66

1.12

1.45

1.88

1.51

1.80

1.76

1.02

<0.001

0.56

0.43

0.037

0.47

<0.001

Data represents %/year


Most common adverse events

Dabigatran 110 mgDabigatran 110 mg%%


WarfarinWarfarin%%

Dyspepsia* 11.8 11.3 5.8

Dyspnea 9.3 9.5 9.7

Dizziness 8.1 8.3 9.4

Peripheral edema 7.9 7.9 7.8

Fatigue 6.6 6.6 6.2

Cough 5.7 5.7 6.0

Chest pain 5.2 6.2 5.9

Arthralgia 4.5 5.5 5.7

Back pain 5.3 5.2 5.6

Nasopharyngitis 5.6 5.4 5.6

Diarrhea 6.3 6.5 5.7

Urinary tract infection 4.5 4.8 5.6

Upper respiratory tract infection 4.8 4.7 5.2

*Occurred more commonly on dabigatran p<0.001


Net clinical benefit and components

CharacteristicCharacteristicDabiDabi

110 mg110 mgDabiDabi

150 mg150 mgWarfarinWarfarin

PP--valuevalue

110 vs. W110 vs. WPP--valuevalue

150 vs. W150 vs. W

Number of patients (n) 6015 6076 6022

Net Clinical Benefit 7.09 6.91 7.64 0.10 0.04

- Stroke / SSE

- Death

- MBE

- PE

- MI

1.53

3.75

2.71

0.12

0.72

1.11

3.64

3.11

0.15

0.74

1.69

4.13

3.36

0.09

0.53

<0.001 (NI)

0.34 (sup)

0.13

0.003

0.56

0.07

<0.001 (NI)

<0.001 (sup)

0.051

0.31

0.21

0.048

All data represents %/year

Connolly SJ., et al. NEJM 2009

BackgroundRivaroxaban

� Direct, specific, competitive factor Xa inhibitor

� Half-life 5-13 hours

� Clearance :� 1/3 direct renal excretion

� 2/3 metabolism via CYP 450 enzymes

� Oral, once daily dosing without need for coagulation monitoring

� Studied in >25,000 patients in post-op, DVT, PE and ACS patients

Rivaroxaban

XaXa

IIaIIa

TF/VIIaTF/VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

Adapted from Weitz et al, 2005; 2008

Rivaroxaban Warfarin

Primary Endpoint: Stroke or non-CNS Systemic Embolism

INR target - 2.5

(2.0-3.0 inclusive)

20 mg daily

15 mg for Cr Cl 30-49 ml/min

Atrial Fibrillation

Randomize

Double Blind /

Double Dummy

(n ~ 14,000)

Monthly Monitoring

Adherence to standard of care guidelines

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 - Preliminary demographics

� 14,269 patients randomised

� Over 1,100 sites in 45 countries

� Median age 73 yrs

� 40% female

� 35% VKA naïve at time of randomisation

Fox K et al. Abstract 89267 presented at ESC 2009

Rivaroxaban (N=7081)

Warfarin (N=7090)

CHADS2 Score (mean)

2 (%)

3 (%)

4 (%)

5 (%)

6 (%)

3.48

13

4329

132

3.46

13

4428

122

Prior VKA Use (%) 62 63

Congestive Heart Failure (%) 63 62

Hypertension (%) 90 91

Diabetes Mellitus (%) 40 39

Prior Stroke/TIA/Embolism (%) 55 55

Prior Myocardial Infarction (%) 17 18

Based on Intention-to-Treat Population

Rocket AF: Baseline Demographics


Primary Efficacy OutcomeStroke and non-CNS Embolism

Event Rates are per 100 patient-years

Based on Protocol Compliant on Treatment Population

0

1

2

3

4

5

6

0 120 240 360 480 600 720 840 960

No. at risk:

Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634

Warfarin 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

Cu

mu

lati

ve

ev

en

t ra

te (

%)

Rivaroxaban

Rivaroxaban

better

Warfarin

better

Primary Efficacy OutcomeStroke and non-CNS Embolism


Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations

Key Secondary Efficacy Outcomes


Based on Safety on Treatment Population

A Comparison of RE-LY and ROCKET AFTrial Designs and Outcomes

Drug Rivaroxaban Dabigatran

Site of action Xa (direct) Thrombin

Pro-drug No Yes

Frequency of

administration

OD BD

Tmax 2-4 h 0.5 -2 h

Half-Life 9-13 h 14-17 h

Interactions CyP3A4 Inhibitors GpP

Protein Binding 90% 35%

Renal excretion 66% 85%

Antidote none none

HIT frequency No effects on platelets

Double-Blind vs. Open-Label Studies

Differences in Primary efficacy Outcome in SPORTIF V and SPORTIF III

1. JAMA 2005;293(6): 690-698

2. Lancet 2003;362: 1691-1698

0

1

2

3

Eve

nt

rate

/ye

ar

1.2

1.6

Non-inferior efficacy demonstrated with ximelagatran vs. warfarin

1.6

2.3

SPORTIF V1

Double-blind design

N=3922, p=0.13

SPORTIF III2

Open-label design.

N=3410, p=0.10

Warfarin Ximelagatran

Baseline Characteristics

Characteristic Dabigatran Rivaroxaban

Randomized 6000 7000

Mean age (years) 71 73

Male (%) 64 60

CHADS2 score (mean)

0-1 (%)2 (%)3+ (%)

2.1

32.634.732.7

3.5

01387

Prior stroke/TIA (%) 20 55

Prior MI (%) 17 17

CHF (%) 32 62

Baseline ASA (%) 40 20

Warfarin Naïve (%) 50 40

C. Michael Gibson, M.S., M.D. Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151

Comparison of Trial MetricsComparison of Trial Metrics

RE-LY Rocket AF

Countries 44 45

Patients 18,113 14,264

Median Duration of Follow-Up

2 years (about 730 days)

589 days of exposure, 707 days including period off drug during follow-up

Time in Therapeutic Range (TTR)

64%67% warfarin-experienced61% warfarin-naïve

57.8%

C. Michael Gibson, M.S., M.D. Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151

Impact of Enrolling Higher CHADs Score Patients

Higher CHADs scores are associated with:

1.Higher rates of major bleeding

2.Lower TTRs3.Greater risk of stroke or SE

C. Michael Gibson, M.S., M.D. Personal communication RE-LY Investigators. Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151

Rates of Drug Discontinuation

RE-LY

1 Year:

Dabigatran 110 mg: 14.5%


Warfarin: 10.2%

2 Years:


Dabigatran 150 mg: 21.2%,

Warfarin: 16.6%


Most common adverse events



WarfarinWarfarin%%

Dyspepsia* 11.8 11.3 5.8

Dyspnea 9.3 9.5 9.7

Dizziness 8.1 8.3 9.4

Peripheral edema 7.9 7.9 7.8

Fatigue 6.6 6.6 6.2

Cough 5.7 5.7 6.0

Chest pain 5.2 6.2 5.9

Arthralgia 4.5 5.5 5.7

Back pain 5.3 5.2 5.6

Nasopharyngitis 5.6 5.4 5.6

Diarrhea 6.3 6.5 5.7

Urinary tract infection 4.5 4.8 5.6

Upper respiratory tract infection 4.8 4.7 5.2

*Occurred more commonly on dabigatran p<0.001


Adverse Events and Liver Enzyme Data

Values are N (%)

Based on Safety Population

Rivaroxaban (N=7111)

Warfarin (N=7125)

Any Adverse EventAny Serious Adverse EventAE leading to study drug discontinuation

82.437.315.7

82.238.215.2

EpistaxisPeripheral edemaDizzinessNasopharyngitisCardiac failureBronchitisDyspneaDiarrhea

10.16.16.15.95.65.65.35.3

8.66.26.36.45.95.95.55.6

ALT Elevation>3 x ULN>5 x ULN>3 x ULN and T Bili > 2 x ULN

2.91.00.4

2.91.00.5

Conclusions

� New agents may make risk reduction in AF easier.

� Newer agents are equally effective at reducing stoke risk with lower bleeding risk, or

� More effective with equal bleeding risk

� New agents bring new side effects

� Economic analysis yet to be considered

� 1st patient to go into A&E with a bleed!!

� Unknown benefit/risk with triple therapy

Pending Questions

� Interactions: drugs and food?

� Association with antiplatelet agents?

� Sub group of patients - Elderly patients?

� Renal insufficiency?

� Liver toxicity?

� Other indications? Valvular prosthesis?

� Lack of Monitoring/adherence – BD vs OD?

� How to deal with bleed?

� Cost may be deciding factor for choice!!

RE-LY vs ROCKET AF

Sotiris Antoniou

Consultant Pharmacist, Cardiovascular Medicine

Barts and the London NHS Trust &

North East London Cardiovascular & Stroke Network

sotiris antoniou consultant pharmacist, cardiovascular ... · new oral anticoagulants sotiris...

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