New Anticoagulants in Non-Valvular AF - isim · slide may be used with external audiences in local BMS/Pfizer arranged meetings ... Non-valvular AF Valvular AF* ... valvular disease

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New Anticoagulants in Non-Valvular AF Efficacy and Safety RE-LY ROCKET-AF ARISTOTLE

2013יולי , כנס האיגוד הישראלי לרפואה פנימית

ח בילינסון"בי, מנהל מחלקה פנימית ג, ר אבישי אליס"ד


ATRIAL FIBRILLATION = EMBOLI

RISK SCORING


ESC 2012 recommendations – Choice of anticoagulant

Adapted from Camm et al. Eur Heart J 2012;e-published August 2012, doi:10.1093/eurheartj/ehs253.

Non-valvular AF Valvular AF*

<65 years & lone AF (including female) No

Assess risk of stroke (CHA2DS2-VASc score)

0 1 ≥2

Assess bleeding risk (HAS-BLED score) Consider patient values and preferences

No antithrombotic therapy

NOAC**

VKA

Yes

**NOAC should be considered instead of VKA (INR 2–3) for most patients with AF.

*Includes rheumatic valvular disease and

prosthetic valves

VKA

OAC therapy


The CHA2DS2-VASc scheme was adopted by the ESC to complement the CHADS2 scoring system

CHADS2 Score CHA2DS2-VASc Score Congestive heart failure 1 Congestive heart failure/left ventricular dysfunction 1

Hypertension 1 Hypertension 1

Aged ≥75 years 1 Aged ≥75 years 2

Diabetes mellitus 1 Diabetes mellitus 1

Stroke/TIA/TE 2 Stroke/TIA/TE 2

Maximum score 6 Vascular disease (prior MI, PAD, or aortic plaque) 1

Aged 65-74 years 1

Sex category (i.e. female gender) 1

Maximum score 9

Camm et al. Eur Heart J 2010;31:2369-429.

CHA2DS2-VASc: In patients with a CHADS2 score of 0-1, or When a more detailed stroke risk assessment is indicated


ESC 2012 recommendations – Choice of anticoagulant

Adapted from Camm et al. Eur Heart J 2012;e-published August 2012, doi:10.1093/eurheartj/ehs253.

Non-valvular AF Valvular AF*

<65 years & lone AF (including female) No

Assess risk of stroke (CHA2DS2-VASc score)

0 1 ≥2

Assess bleeding risk (HAS-BLED score) Consider patient values and preferences

No antithrombotic therapy

NOAC**

VKA

Yes

**NOAC should be considered instead of VKA (INR 2–3) for most patients with AF.

*Includes rheumatic valvular disease and

prosthetic valves

VKA

OAC therapy


VKA therapy has several limitations

Considerable variability in dose-response

(genetic variations)1

Long half-life Slow onset and offset

of action1,2

Interactions with drugs and diet1

Narrow therapeutic window (INR range 2-3)1

Risk of stroke Risk of bleeding1

Convenience not optimal: Frequent coagulation

monitoring1

Frequent dose adjustments1

Issue in perioperative anticoagulation (bridging)2

1. Weitz et al. Eur J Haematol 2010;85 (Suppl 72);1-28. 2. Camm et al. Eur Heart J 2010;31:2369-429.


The risks of ischaemic stroke or intracranial bleed are high outside a narrow INR range

20

15

10

5

1

Odd

s Rat

io

1.0 INR 2.0 3.0 4.0 5.0 6.0 7.0 8.0

Intracranial bleeding risk

Ischaemic stroke risk

Ischaemic stroke risk Intracranial bleeding risk

Adapted from: Fuster et al. Circulation 2011;123:e269-e367. Hylek and Singer. Ann Intern Med 1994;120:897-902. Oden et al. Thromb Res 2006;117:493-9.

Adjusted odds-ratio for ischaemic stroke and intracranial bleeding in relation to intensity of anticoagulation


VKA therapy has several limitations

Considerable variability in dose-response

(genetic variations)1

Long half-life Slow onset and offset

of action1,2

Interactions with drugs and diet1

Narrow therapeutic window (INR range 2-3)1

Risk of stroke Risk of bleeding1

Convenience not optimal: Frequent coagulation

monitoring1

Frequent dose adjustments1

Issue in perioperative anticoagulation (bridging)2

1. Weitz et al. Eur J Haematol 2010;85 (Suppl 72);1-28. 2. Camm et al. Eur Heart J 2010;31:2369-429.

9

The INR for VKAs is often outside the therapeutic range: international study of anticoagulation management

Tim

e in

targ

et ra

nge

(%)

0

20

40

60

80

100

US Canada France Italy Spain

INR <2 INR 2–3 INR >3

Ansell J et al. J Thromb Thrombolysis 2007;23:83–91

The predominant vitamin K antagonist (VKA) in use was warfarin in the US, Canada and Italy; acenocoumarol in Spain; and fluindione in France; INR = international normalized ratio

Warfarin for Atrial Fibrillation Limitations Lead to Under-treatment

0

20

40

60

80

<55 55-64 65-74 75-84 ≥85

44%

58% 61% 57%

35%

Age (years)

War

farin

Use

in

Elig

ible

Pat

ient

s (%

) 55% Overall Use

Go A et al. Ann Intern Med 1999;131:927.


Patients stop taking warfarin over time

Age 40-64

Age 75-79

Age 65-69

Age 80-84

Age 70-74

Age 85+

Patient age

0

20

40

60

80

100

Patie

nts

(%)

0 2 4 6 Time (years after starting treatment)

1

Adapted from Gallagher et al. J Thromb Haemost 2008;6:1500-6

~30% of AF patients treated with warfarin discontinued within 1 year (from a total population of 41,910 AF patients in the UK General Practice Research Database

EU API234 Subject to local prior approval by BMS/Pfizer, as per relevant SOP and local rules, slide may be used with external audiences in local BMS/Pfizer arranged meetings 12


NEW ORAL ANTICOAGULANTS

NOACS

13

Copyright ©2011 American Heart Association

Hankey, G. J. et al. Circulation 2011;123:1436-1450

Illustration showing the sites of action of new anticoagulants in the coagulation cascade


השוואה בין התכשירים

15

16 For medical non-promotional reactive use only

Clinical pharmacology of apixaban, rivaroxaban and dabigatran

Apixaban1 Rivaroxaban2 Dabigatran3

Mechanism of action Direct factor Xa inhibitor

Direct factor Xa inhibitor

Direct thrombin inhibitor

Absolute availability ~50% 80–100% ~6.5% Route of administration Oral Oral Oral

Pro-drug No No Yes Food effect No No No

Renal clearance ~27% ~33 % 85%

Mean half-life (t1/2)

~12 h

7–11 h ~12–14 h

Tmax 3-4 h 2–4 h 0.5–2 h

1. Apixaban SmPC June 2011 2. Rivaroxaban SmPC March 2011 3. Dabigatran SmPC August 2011

No head-to-head comparisons between apixaban, rivaroxaban and dabigatran have been performed in a randomised clinical trial setting. The information in this table is based on the SmPCs for apixaban, rivaroxaban and dabigatran. Please refer to the SmPCs for further information.

Phase III trials vs warfarin (aim INR 2.0-3.0)

RELY ROCKET ARISTOTLE Sample size 18,113 14,266 18,201

New treatment Dabigatran 110mg BID

Dabigatran 150mg BID

Rivaroxaban 20mg

QD

Apixaban 5mg

BID

Design Non-inferiority

PROBE

Non-inferiority

Double-blind

Non-inferiority

Double-blind

Patients AF + CHADS2 ≥ 1 AF + CHADS2 ≥ 2 AF + CHADS2 ≥ 1

Primary outcome Stroke (ischemic or hemorrhagic) or systemic embolism

Stroke (ischemic or hemorrhagic) or systemic embolism

Stroke (ischemic or hemorrhagic) or systemic embolism

Safety outcome Primary: Major Bleeding

Secondary: Major Bleeding + CRNM

Primary: Major Bleeding


Primary: Major Bleeding


Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011; ENGAGE- AF Study Investigators. AHJ 2010

P

Superiority

P

Non-

inferiority

HR

(±CI)

Warfarin

N (%/yr)

Study

medication

N (%/yr)

Medication Study

0.34 <0.001 0.91

(0.74-1.11)

199

(1.69)

182

(1.53)

Dabigatran

110 mg BID

RE-LY

<0.001 <0.001 0,66

(0.53-0.82)

134

(1.11)

Dabigatran

150 mg BID

<0.001 0.88

(0.75-1.03)

306

(2.4*)

269

(2.1*)

Rivaroxaban

20 mg (15 mg) QD

ROCKET-AF

ITT

0.12 <0.001 0.79

0.66-0.96)

241

(2.2*)

188

(1.7*)

Per protocol,

As Treated

0.01 <0.001 0.79

(0.66-0.95)

265

(1.60)

212

(1.27)

Apixaban

5 mg (2.5 mg) BID

ARISTOTLE

Primary End-points – Stroke & Systemic Emboli

New antithrombotic therapies compared to warfarin Stroke or systemic embolism

Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011

Favors NOAC Favors warfarin

New antithrombotic therapies compared to warfarin Stroke of ischemic or unknown origin



New antithrombotic therapies compared to warfarin All-cause mortality



New antithrombotic therapies compared to warfarin Major bleeding



New antithrombotic therapies compared to warfarin Gastrointestinal bleeding



New antithrombotic therapies compared to warfarin Intracranial hemorrhage



New antithrombotic therapies compared to warfarin Myocardial infarction



EU API234 Subject to local prior approval by BMS/Pfizer, as per relevant SOP and local rules, slide may be used with external audiences in local BMS/Pfizer arranged meetings 26

Sebastian Sc, et.al, Circ Cardiovasc Qual Outcomes July (2012)

Patients with CHADS2 ≥3 Results:

New Anticoagulants in Atrial Fibrillation

New Anticoagulants in Atrial Fibrillation

New anticoagulants compared to warfarin in AF 2011


Effet on outcome event D150 D110 Riva Apix

Superiority stroke √ √

Reduction hemorrhagic stroke √ √ √ √

Reduction mortality (√) √

Reduction major bleeding √ √

Increase gastrointestinal bleeding √ √

Increase myocardial infarction (√) (√)

Number of benefits compared to warfarin 3 2 1 4

מינון-?אחת ליום לעומת פעמיים*

?מה עושים אם שוכחים מנה*


144 150 156 162 1680

50

100

150

200

250

Api

xaba

n Pl

asm

a C

once

ntra

tion

(ng/

mL)

Time (hours)

The apixaban 5 mg BD regimen demonstrates a lower peak:trough ratio compared with apixaban 10 mg OD

Time (h)

Apix

aban

con

cent

ratio

n (n

g/m

L)

Mean plasma concentration following multiple oral doses

5 mg BD 10 mg OD

Frost et al. J Thromb Haemost 2007; 5 Supplement 2: P-M-664. Data on File API-001


Simulated plasma concentration-time profiles for apixaban 5 mg BID2

Time after the first dose (hours)

Apix

aban

con

cent

ratio

n (n

g/m

L)

50

100

150

200

150 160 170 180 190

Administered as intended

With a missed Dose administered 6 h before the next scheduled dose

With a missed dose administered along with the next scheduled dose

Without replacing the missed dose

If a dose is missed, patient should take apixaban immediately and then continue with twice daily intake as before1

1. Apixaban SmPC 2012 2. Data on file API-003

All new agents compared with warfarin

Advantages: • No monitoring

required • No variability • Fast onset of action • Fast offset • Lower IC hemorrhage

rates (about 50% lower for all)

Disadvantages: • No reversibility • No monitoring • Expensive (higher tier

by PBM) • Not once-daily in AM • Less clinical

experience • No data for cardiac

issues other than NVAF

Indirect comparison of dabigatran, rivaroxaban and apixaban for AF

* The available data indicate no significant difference in efficacy between dabigatran 150 mg and apixaban for the prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation. * However, apixaban is associated with less major bleeding than dabigatran 150 mg or rivaroxaban. * Rivaroxaban is less effective than dabigatran 150 mg in preventing stroke or systemic embolism. *Low renal clearance by apixaban.

Such an indirect comparison should be used only to generate hypotheses, which need to be tested in a dedicated randomized trial comparing the three drugs directly.

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New Anticoagulants in Non-Valvular AF - isim · slide may be used with external audiences in local BMS/Pfizer arranged meetings ... Non-valvular AF Valvular AF* ... valvular disease