I DOA Sono Tutti Uguali?

Quale Farmaco Per

Quale Paziente

Gianluca Botto, MD,

FAAC, FESC

UO Elettrofisiologia

Ospedale Sant’ Anna, Como

Presenter Disclosure Information

Research support:

Boston Scientific, Medtronic; St. Jude Medical, Bayer

Healthcare, Daijchi, Gilead, Sanofi

Advisory Board:

Biotronik, Medtronic; St. Jude Medical, MSD, Bayer

Healthcare, Boehringer, BMS, Pfizer, Sanofi

Speaker Fees:

Boston Scientific, Medtronic, St. Jude Medical, Sorin

Group, Bayer Healthcare, Boehringer, BMS, Meda,

MSD, Pfizer, Sanofi

The Promise of NOAs

Anticoagulation in AFWhat Was The Situation in 2009 ?

■ Treatment recommendation from 2006 ACC/AHA/ESC GLs 1

- CHADS2 score >1: VKA- CHADS2 score =1: ASA or VKA- CHADS2 score >0: ASA or nil

■ Only 50-60% of eligible pts were receiving VKA 2

■ Of those receiving VKA, average TTR was often below 50% 3

►Majority of pts were suboptimally treated

►Need for large RCTs that was representative of clinical practice

1-Fuster V. Circulation 2006; 2-Go AS. Ann Intern Med 1999; 3-Reynolds MW Chest 2004

Desirable Qualities of a New

Anticoagulant

• Oral

• Fixed dosing

• Rapid onset and offset of action

• Predictable anticoagulant response (no monitoring)

• Minimal food and drug interactions

• As or more effective than current agents

• As or safer than current agents

• More cost-effective than current Rxs

• Reversible

7

Mean 2,1 Mean 2,1 Mean 3,5 Mean 2,8

XANTUS: Incident Rate of

Stroke/SE, Major Bleeding and All-Cause Death by CHA2DS2-VASc Score

174 685 1313 1578 1405 837 789 6781

CHA2DS2-VASc score

Patients (n)

Camm AJ. Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466;

Indirect

Comparison

of NOAs in

Pts with AFA Network Meta-analisys

Harenberg J. Int Angiol 2012; 31: 330-9

Po

inte

rs T

ow

ard

s W

hic

h N

OA

Cs

to C

ho

ose

High risk of bleedinge.g. HAS-BLED ≥3

Agent/dose with the lowest rate of bleeding

ApixabanDabigatran 110Edoxaban 30

Previous GI bleeding or high risk of GI bleed

Agent with the lowest incidence of GI bleed

Apixaban

High risk of ischemic stroke, low risk of bleeding

Agent/dose with the best reduction of ischemic stroke Dabigatran 150

Previous StrokeBest investigated agent or the greatest reduction of 2° stroke

ApixabanRivaroxaban

CAD, previous MI, high risk of ACS/MI

Agent with a positive effect in ACS Rivaroxaban

GI upset/disorders Agent/dose with no reported GI effectsApixabanRivaroxaban (J)

Patient preference Agents with OD formulation RivaroxabanEdoxaban

Cardioversion/ablation Agents tested in RCTs Rivaroxaban

Renal impairmentAgent least dependent on renal function

ApixabanRivaroxaban

Specific pt characteristics Consider … NOACs

Efficacy

Allocation to a NOAs significantly reduced the composite of

stroke or systemic embolic events by 19% as compared to WRF

The overall beneficial effect was mainly driven by a large

reduction in haemorrhagic stroke(RR on combined data: 0.49, 95%CI: 0.38-0.64, P

Safety

NOACs IntraCranial Haemorrage

Outcome

vs

Warfarin

RE-LY

Dabigatran

150 mg BID

HR

(95% CI)

ROCKET-AF

Rivaroxaban

20 mg OD

HR

(95% CI)

ARISTOTLE

Apixaban

5 mg BID

HR

(95% CI)

ENGAGE-AF

Edoxaban

60 mg OD

HR

(95% CI)

ICH 0.40

(0.27-0.60)

P

Stroke/Thromboembolism and Intracranial Hemorrhage

in a Real-World AF Population The Complications of Atrial Fibrillation in the Bologna Area (CAFBO) Study.

Palareti G. CHEST 2014

20 pts with ICH

median age 82 ys

W 65%, ASA 30%

95% in pts > 70 yrs

85% occur with an INR in

2.0-3.0 range

45% in-H mortality

17% major deficit

Ruff CT Lancet dec 2013 early on line pub modif

Secondary Safety Outcomes

-Poor outcome

(30-day mortality = 48.6%)

-High cost

(30% more than ischemic stroke)

US Department of Defense database mirrors the favourable

dabigatran profile seen in RE-LY® and FDA Medicare data

MORTALITY

Warfarin

D150 BID

DoD*1Warfarin

D150 & D75 BID

combined

EV

EN

T R

AT

E (

% P

ER

YE

AR

)

INC

IDE

NC

E R

AT

E P

ER

10

0P

ER

SO

N-Y

EA

RS

STROKEISCHAEMIC

STROKEICH

MAJOR

BLEEDINGMI

HR: 0.64

P

Major Bleeding in Patients With NV-AF Pharmacovigilance Study of 27467 Pts Taking Rivaroxaban

■ From Jan 2013, to Mar 2014,

US- DoD electronic HC records

■ 496 MB events in 478 pts,

incidence of 2.86 per 100 person-yrs

■ MB was most commonly GI (88.5%) or ICl (7.5%)

■ 46.7% of MB pts received a transfusion,

none any type of clotting factor

■ 14 pts died during their MB hospitalization,

fatal bleeding incidence rate of 0.08 per 100 pts/y

Tamayo S. Clin. Cardiol. 2015; 38: 63-68

Cost-Efficacy

Anticoagulation Rx in Pts With NV-AF

Projected Costs, Cost-Efficacy and Cost-Benefit

Harrington AR. Stroke 2013 in press

Antidote

Po

llack

CV

et a

l. N

Eng

JM

ed

2015

ANNEXA-A / ANNEXA-R

- Apixaban

- Rivaroxaban

I DOA Sono Tutti Uguali?

Quale Farmaco Per

Quale Paziente

Gianluca Botto, MD,

FAAC, FESC

UO Elettrofisiologia

Ospedale Sant’ Anna, Como

Characteristics of NOAs Comparison With Warfarin

WARFARIN DABIGATRAN RIVAROXABAN APIXABAN EDOXABAN

Target Vitamin K-dep.

clotting factors II,

VII, IX,and X

Thrombin Factor Xa Factor Xa Factor Xa

Bioavailability (%) >95 ∼6 >80 (with food) >50 >60 (85 with food)

Intake with food

recommended ?

NO NO Mandatory NO No official

recommendation

Absorption with

H2B/PPI ?

NO -12%-30% NO NO NO

Time to peak

activity (hs)

72-96 1-3 2,5-4 3-4 1-2

Half life (hs) 40 12-17 5-9 (young healty)

11-13 (elderly)

8-15 9-11

Dosing frequency OD BID OD BID OD

Interaction with

drugs

Numerous drugs

including substrates

of CYP2C9,

CYP3A4, CYP1A2

Strong P-gp

inhibitors

and inducers

Strong CYP3A4

inducers, strong

inhibitors of both

CYP3A4 and P-gp

Strong inhibitors

and inducers of

both CYP3A4 and

P-gp

Strong P-gp

inhibitors

and inducers

Interaction with

food

YES NO NO NO NO

Renal elim (%)

Putting it All TogeteherWhat Should We Do Now in Clinical Practice ?

■ GI bleeding

■ Elderly and fragile pts

■ Effect of renal funcion

■ Perioperative management

■ Daily dosage (OD vs BID)

■ Drug Interaction

■ ACS/MI

NOAs in Clinical PracticeIdentifyng Pts with Increased Bleeding Risk

■ Patient-related factors

- advanced age (≥80 ys)

- low body weight (≤60 Kg)

- renal impairment / fluctuation in renal function

- GI-related comorbidities

■ Clinical Considerations

- examine creatinine clearance rates

(not just serum creatinine)

- use of antiplatelet Rx

EHRA Practical GL. Europace 2013; 15: 625-651

NOACs Bleeding

Outcome

vs

Warfarin

RE-LY

Dabigatran

150 mg BID

HR

(95% CI)

ROCKET-AF

Rivaroxaban

20 mg OD

HR

(95% CI)

ARISTOTLE

Apixaban

5 mg BID

HR

(95% CI)

ENGAGE-AF

Edoxaban

60 mg OD

HR

(95% CI)

GI

Bleeding

1.50

(1.19-1.89)

1.39

(1.19-1.61)

0.89

(0.70-1.15)

1.23

(1.02-1.50)

Major

Bleeding

0.93

(0.81-1-07)

1.04

(0.90-1.20)

0.69

(0.60-0.80)

1.23

(0.71-0.91)

Dabigatran in

“Real-World”

Pts With AFData From The

DANISH Registry

■ 2:1 PS Analysis

■ D 4978

■ W 8936

Larsen TB.

JACC 2013; 61: 2264-73

Comparison of Main Outcomes:

XANTUS versus ROCKET AF

CHADS2 Prior stroke#

ROCKET AF1 3.5 55%

XANTUS2 2.0 19%

#Includes prior stroke, SE or TIA; *Events per 100 patient-years

1. Patel MR et al, N Engl J Med 2011;365:883–891; 2. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466

Apr 2012

Clin Pharmacokinet 2010; 49: 259-68.

Apr 2012

Noacs In Renal Dysfunction Approved European Labels And Dosing In CKD

Apr 2012

NOACs Cessation Before Planned Surgery

EHRA Practical GL. Europace 2013; 15: 625-651

Dosing Considerations Update Under Review

Courtesy of H. Heidbuchel and J. Camm

Patients’

Preferences For

Type 2 Diabetes

Treatment Dosing

Schedules

Hauber AB.

Patient Preference and Adherence

2013:7 937–949

Coleman CI. Curr Med Res Opin 2012; 28: 669-680

Daily Dosing Frequency and Adherence Among NVAF Pts

26% higher likelihood

of adherence with OD

dosing regimen

1. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466; 2. Piccini JP et al, Eur Heart J 2014; 35(28):1873-80;

3. Beyer-Westendorf J et al, Blood 2014; 124(6):955-62

XANTUS: Treatment Persistence and Patient Satisfaction

Persistence with rivaroxaban in XANTUS was 80% at 1 year

Over 75% of patients were ‘very satisfied/satisfied’ with their

treatment

Nonadherence to a NOAC is

Associate to Worse Outcomes

Bleeding Risk With EdoxabanOnce-daily vd Twice-daily Dosing

Edoxaban dose and regimens

Ble

edin

g incid

ence (

%)

Weitz JI. Thromb Haemost 2010; 104: 633-641

Rivaroxaban Dosing

Overlap B/ween od and bid Regimens• The Cmax and Ctrough of rivaroxaban increased in a dose-dependent manner with both dosing

regimens up to 20 mg (total daily doses).

• The 90% intervals for Cmax and Ctrough overlapped between the two dosing regimens.

100

200

300

400

05 10 15 20

Rivaroxaban daily dose (mg)

Riv

aro

xa

ba

n C

max

(μg

/l)

bid

od

5 10 15 20

120

100

80

60

40

20

0

Rivaroxaban daily dose (mg)

Riv

aro

xa

ba

n C

thro

ug

h(μ

g/l

)

bid

odCmax Cthrough

Mueck W. Thromb Haemost 2008;100:453–461

Novel Oral Anticoagulants

NOAs all provide important advantage over W, including convenience, at least as effective preventionof stroke, and less intracranial hemorrhage

Until head-to-head trials or large scale observationalstudies that reflects routine use of these agents are available, indirect comparison are just one tool for hypothesis generating

Growing clinical practice data, despite differences in selection, treatment and management of pts, supportthe efficacy and safety profile of NOACs