Rivaroxaban: efficacia e sicurezza dei NAO · Dose totale giornaliera 120 mg * ... AF who are...

Stefano Carugo

Università degli Studi di Milano

Rivaroxaban: efficacia e sicurezza dei NAO

Alba 15 novembre 2014

• All four novel anticoagulants are non-inferior to warfarin in reducing the

risk of stroke and systemic embolization

• All four novel anticoagulants are associated with a reduction of

haemorrhagic stroke

• All four agents reduce the risk of bleeding (fatal and in critical organ for

Rivaroxaban, major for Apixaban and Edoxaban, major at 110 mg for

Dabigatran, ) and intracranial hemorrhage

• The directionality and magnitude of the mortality reduction is consistent

and approximates a RRR of 10% / year

“Class effects”

• Dabigatran (at the dose of 150 mg bid) is associated with a reduction of

ischemic stroke

• Rivaroxoban is associated with a reduction the risk of fatal and in

critical organ bleeding

• Apixaban is associated with a reduction of mortality

• Both doses of edoxaban are associated with a reduction of major bleeding

AF studies: main clinical differences

Ruff et a,l 2013

All Stroke or Systemic Embolism

Comparison with VKA

Ruff et al 2013

Major bleeding

Ruff et al 2013

Secondary efficacy and safety outcomes

ESC 2012 Guidelines: Recommendations for New OACS

• Dabigatran 150 mg bid

• Dabigatran 110 mg bid in:

• ≥ 80 years

• Concomitant use of

interacting drugs

• HAS-BLED ≥ 3

• CrCl 30-49 mL/min

• Peri-cardioversion

• No recommendation in

severe renal impairment

CrCl < 30 mL/min

• Apixaban



CrCl <30 mL/min

• No recommendation for

cardioversion *

• No specific

recommendations due to

regulatory approval

status

All NOACs are recommended for SPAF in patients at risk of stroke

(CHA2DS2-VASc≥2) in preference over a VKA

• Rivaroxaban 20 mg od

• Rivaroxaban 15 mg od

with:

• HAS-BLED ≥3

• CrCl 30-49 mL/min



CrCl < 30 mL/min

• No recommendation for

cardioversion*

Camm AJ et al. Eur Heart J 2012; od=once daily; bid=twice daily*based on lack of published data

ESC 2012 Guidelines: Selection of Patients for OACs

Non-valvular atrial fibrillation Valvular atrial fibrillation

< 65 years and lone AF including women

Stroke risk assessment using CHA2DS2-VASc

0 1 ≥2

Assess bleeding risk (HAS-BLED score);

consider patient values/preferences

New oral anticoagulant;

rivaroxaban, dabigatran

apixaban

Vitamin K antagonistNo antithrombotic therapy

Oral anticoagulant

Yes

Camm AJ et al. Eur Heart J 2012 Slide line preferred; dotted line alternative

Dati farmacodinamici e clinici

Aspetti pratici (aderenza)

Monosomministrazione

quotidiana: vantaggi

Rivaroxaban (MW 436 1 nM = 0.436 ng/mL)

inibisce:

– attività FXa libero = IC50 0.7 nM

– attività protrombinasi = IC50 2.1 nM

Ctrough (concentrazioni dopo 24 h) con 10 mg

0.45–0.73 ng/ml [≈1-1.7 nM] Ctrough (concentrazioni dopo 24 h) con 20 mg

1.5–2.4 ng/ml [≈3.5-5.5 nM]

Rivaroxaban:

farmacodinamica regime OD

La concentrazione minima nelle 24 h è sempre

sufficiente a inibire adeguatamente il FXa

• La somministrazione monogiornaliera (OD) si associa a una superiore

concentrazione massima (Cmax) e a una minore concentrazione minima

(Ctrough) rispetto alla somministrazione bigiornaliera (BID), con

sovrapposizione tuttavia degli intervalli di variabilità al 90%.

• La somministrazione OD risulta pertanto simile a quella BID relativamente

alla concentrazione plasmatica (e quindi all’effetto farmacologico), ma più

conveniente per il paziente.

Riv

aro

xa

ba

n C

max

(µg

/l)

Dose giornaliera totale di rivaroxaban (mg) Dose giornaliera totale di rivaroxaban (mg)

Riv

aro

xaban C

max

(µg

/l) Riv

aro

xa

ba

n C

troug

h (µ

g/l) R

iva

roxa

ba

n C

troug

h (µ

g/l)

Studio BID Cmax

Studio OD Cmax

Studio BID Ctrough

Studio OD Ctrough

Dosaggio di rivaroxaban od versus bidin pazienti sottoposti a protesi d’anca

Mueck, Thromb Haemost, 2008

AUC, area under the plasma

concentration-time curve from

0 to 24 hours at steady-state;

Cmax, maximum steady-state

plasma concentration;

Cmin, minimum steady-state

concentration;

QD, once daily;

BID, twice daily

300

250

200

150

100

50

0

ng/m

L

30

QD

60

QD

30

BID

60

BID

30

QD

60

QD

30

BID

60

BID

30

QD

60

QD

30

BID

60

BID

4000

3000

2000

1000

Ng*h

/mL

150

100

50

0

ng/m

L

Cmax, 88 AUC, 88 Cmin, 88

35

30

25

20

15

10

5

0Ble

ed

ing incid

ence, %

30

QD

60

QD

30

BID

60

BID

Edoxaban

Weitz, Thromb Haemost, 2010

I valori a valle piuttosto che al picco sono i migliori indicatori di rischio di sanguinamento

Anche i risultati dello studio di fase II con edoxaban

sostengono la selezione del dosaggio od nella AF

Weitz, Thromb Haemost, 2010

35

30

15

25

20

10

5

0

Dose di edoxaban ed intervallo di dosaggio

Inc

iden

za d

i san

gu

inam

en

to (

%)

30 mg od 60 mg od 30 mg bid 60 mg bid

Dose totale giornaliera

60 mg


30 mg


120 mg *

*Stopped prematurely by the DSMB

Dati farmacodinamici e clinici

Aspetti pratici (aderenza)

Monosomministrazione

quotidiana: vantaggi

A systematic review of the association between dose

regimens and medication compliance

Claxton, Clin Ther , 2001

0

5

10

15

20

25

La compliance del regime od rispetto al regime bid è

generalmente migliore in condizioni croniche

Numero di studi che valutano direttamente la complianceN

um

ero

di

stu

di

od > bid* od = bid# od < bid‡

* La compliance del paziente (valutata nello studio) con regime od è significativamente migliore rispetto al

regime bid# Nessuna differenza significativa nella compliance del paziente (valutata nello studio) tra regime od e bid‡ La compliance del paziente (valutata nello studio) con regime bid è significativamente migliore rispetto al

regime od

Ricerca Pubmed; Marzo 2001–2011

Barriers to adherence (patients survey):

Forget

Other priorities

Decision to quit dose

Lack of information

Emotional reasons

Improve adherence:

Emphasizing value of regimen

Simple regimen

Adapt regimen to patient´s lifestyle

Quali fattori causano una scarsa aderenza alla

terapia e quali la potrebbero migliorare

Osterberg et al. N Engl J Med 2005;353:487-97; Song et al. Am J Cardiovasc Drugs 2012; 12 (4): 245-253.

93,1

84,9

76,3

86,2

73,8

50,4

0

20

40

60

80

100

Taking Adherence Regimen

Adherence

Timing Adherence

Ad

here

nce (

%)

Once-daily

Twice-daily

Il regime OD è associato a una maggior aderenza alla

terapia

- 6.9 (-11.2,-2.6)

P<0.01- 14.0 (-19.9,-8.1)

P<0.01

- 22.9 (-33.1,-12.7)

P<0.01

Coleman CI et al. Curr Ned Res Opin. 2012;28(5):669-80.

Dosing Frequency

Adherence to Chronic Cardiovascular Disease Medication

Definition of adherenceLess stringent More stringent

Nei pazienti con FA la compliance alla terapia

è migliore con un regime OD rispetto a BID

EHRA Practical Guide, Europace, 2013

I nuovi studi

3030

XANTUS: study design

Interventional observational study in patients with non-valvular AF who are prescribed rivaroxaban under routine treatment conditions to prevent stroke or non-central nervous system

systemic embolism

Rivaroxaban dose and duration of

drug used at discretion of

attending physician

Study population:

patients with non-valvular AF (N~ 6000)

who start treatment

with rivaroxaban to prevent stroke or non-CNS systemic

embolism

Investigators to collect dataat initial visit, at hospital discharge (if

applicable) and quarterlya

N~ 6000

Final visit: 1 yearb

Clinicaltrials.gov NCT01606995

a: protocol does not define exact referral dates for follow up visits or reports (every 3 months recommended)b: in patients discontinuing rivaroxaban before 1 year, the end of observation period is 30 days after last dose

3131

XANTUS: endpoints

Primary endpoints:

• Adjudicated major bleeding events

• Adverse events


Secondary endpoints:

• All-cause mortality

• Adjudicated symptomatic thromboembolic events (collected as adverse events)

• Persistence with rivaroxaban treatment

Anticipated timelines: first patient visit: June 2012

last patient visit: Dec 2014

3232

XALIA: study design

Prospective non-interventional cohort field study to collect real-life data on adverse events, bleeding, thromboembolic events

and mortality in patients diagnosed with acute DVT treated with rivaroxaban or standard of care

Rivaroxaban for ≥ 3 months

Type, dose and duration of drug

used at discretion of attending

physician

Study population:

Pts (N~4800) with

disgnosis of acute DVT

(not PE) and with an

indication for

anticoagulant therapy for ≥ 3 months

Investigators to collect dataat initial visit, at 1 month

and then quarterlya

N~ 2400

N~ 2400

SoC: e.g. initial treatment with LMWH orfondaparinux, followed by VKA for ≥ 3 months Final assessment

(1 month after end oftreatment)


a: protocol does not define exact referral dates for follow up visits

3333

XALIA: endpoints

Primary endpoints:

• Major bleeding events

• Symptomatic recurrent venous thromboembolic events

• All-cause mortality



• Adverse cardiac events

• Other symptomatic thromboembolic events

• Treatment satisfaction (patient-reported outcomes)

Anticipated timelines: first patient visit: June 2012

last patient visit: Dec 2014

3434

X-PLORER: study design

Prospective multi-center, randomized, heparin controlled dose finding trial to evaluate the efficacy and safety of rivaroxaban

on the background of standard dual antiplatelet therapy to support elective PCI

Rivaroxaban 20 mg1

Study population: patients with

symptomatic CAD undergoing an elective (non

emergent) PCI on one of the two lesions in the

native coronary vessels3

N= 105

Follow up call


1: single dose 2-4 hours before index PCI procedure2: 5 minutes before PCI (after insertion of catheter sheath) until end of PCI procedure3: all patients on stable DAPT≥5 days before PCI procedure

2:2:2:1

R

Rivaroxaban 10 mg1

Rivaroxaban 10 mg1+ UFH 50 IU/kg bolus2

UFH 70-100 IU/kg bolus2

Index

PCI30+7 days

3535

X-PLORER: endpoints

Primary endpoints: anticoagulant effect determined based on percentage of patients who:

• Require ball-out anticoagulant therapy in the context of an ischemic coronary event, and/or

• Experience an angiopraphic flow-limiting thrombotic event, and/or

• Experience thrombus formation on the PCI equipment, and/or

• Experience a procedural myocardial infarction



• Bleeding events

• Composite of clinical ischemic events up to 30 days after index PCI

• Coagulation profile and plasma concentrations of rivaroxaban

Anticipated timelines: first patient visit: Oct 2011

last patient visit: Q1 2013

3636

X-VERT: study design

Prospective , phase IIIb, randomized, open label, parallel group, active controlled study exploring efficacy and safety of rivaroxaban (20 mg

OD) compared with dose adjusted VKA for the prevention of CV events in patients with NVAF scheduled for cardioversion

Rivaroxaban 20 mg OD1

Study population: patients with

NVAF lasting >48 hours or of

unknown duration and scheduled for

electrical or pharmacologic cardioversion

Follow up callClinicaltrials.gov NCT01674647

1: CrCl 30-49 ml/min:15 mg OD

R

card

iove

rsio

n

Sufficient anti-

coagulation OR

immediate TEE

YES: direct cardioversion

NO: delayed cardioversion

2:1

VKA (INR 2-3)

1-5 days


42 days

VKA (INR 2-3)

2:1

R


VKA (INR 2-3)

≥21(+4) days(max 56[+4] days)

card

iove

rsio

n


42 days

VKA (INR 2-3)

SOC

SOC

SOC

SOC

30 days

30 days

N=1500

3737

X-VERT: endpoints

Primary endpoints:

EFFICACY

• Composite of stroke, TIA, non-CNS systemic embolism, MI, cardiovascular death

SAFETY

• Major bleeding



• Composite of stroke and non-CNS systemic embolism

• Composite of stroke, TIA, non-CNS systemic embolism, MI and all-cause mortality

• All bleeding events

Anticipated timelines: first patient visit: Oct 2012


3838

VENTURE-AF: study design

Randomized, open label, active controlled multi-center study to evaluate the safety of rivaroxaban and VKA in subjects

undergoing catheter ablation for atrial fibrillation

Rivaroxaban 20 mg OD

Study population: patients with paroxysmal or

persistent NVAF scheduled to undergo first ever

catheter ablation for their AF

≥ 4 weeks30 ± 5 days

follow up


R

N=250

1:1

VKA (INR 2-3) Cat

het

erab

lati

on

pro

ced

ure

Rivaroxaban 20 mg OD

VKA (INR 2-3)

Day 1 ≥ 4 weeks ≥ 8 weeks

3939

VENTURE-AF: endpoints

Primary endpoints:

•Incidence of major bleeding events 30 ± 5 days after catheter

ablation procedure



•Incidence of the composite and individual components of myocardial infarction, ischemic stroke, NC-systemic embolism, and vascular death, 30 ±5 days after procedure

Anticipated timelines: first patient visit: end of 2012


4040

PIONEER AF-PCI: study design

Open label, randomized, controlled, multi-center study exploring two treatment strategies of rivaroxaban and a dose adjusted oral VKA treatment strategy in patients with AF who undergo

PCI

Clinicaltrials.gov: NCT01830543

Rivaroxaban 15 mg OD*#+ clopidogrel

Study population: patients with paroxysmal, persistent or

permanent AF

N= 2100

End of treatment

(12 months)

*: reduced to 10 mg OD in patients with CrCl 30-50 ml/min#: first dose administered 72-96 h after sheath removal§: first dose administered 12-72 h after sheath removal

1:1:1

R

Rivaroxaban 2.5 mg BID§

+DAPTPCI (with

stent placeme

nt

VKA (target INR 2-3)§

+DAPT

Rivaroxaban 15 mg OD*+ low dose ASA

VKA + low dose ASA

Intended DAPT durationOf 1,6 or 12 months

PIONEER AF-PCI: endpoints

4141

Primary endpoints:

• Composite of TIMI major bleeding, minor bleeding and bleeding requiring medical attention (known collectively as clinically significant bleeding at 12 months


• Separate components of the primary endpoint

• Composite of adverse CV events (cardiovascular death, MI, stroke) at the end of the prespecified duration of DAPT and at month 12

• Stent thrombosis

Anticipated timelines: first patient visit: Apr 2014



4242

COMPASS: study design

Randomized, controlled trial of rivaroxaban for the prevention of major CV events in patients with coronary or peripheral

artery disease


This study will evaluate the efficacy and the safety of rivaroxaban alonecompared with low rivaroxaban+ ASA or ASA alone for the prevention ofmajor adverse cardiac outcomes in patients with established CAD or PAD

• Rivaroxaban: 2.5 mg bid+ ASA 100 mg OD

• Rivaroxaban: 5 mg bid

• ASA: 100 mg od

COMPASS: endpoints

4343

Primary endpoints:

• Composite of CV death, MI and stroke


• Major bleeding

Anticipated timelines: first patient visit: Feb 2013



4444

X-TRA: study design

Open label, international, multi-center, interventional study exploring rivaroxaban for the treatment of a left atrial (LA)/left

appendage (LAA) thrombus in subjects with NVAF or atrial flutter

4444

Study population: patients with NVAF or

atrial flutter with LA/LAA thrombus detected via TEE


N~ 60

End of follow up

1: CrCl 15-49 ml/min: 15 mg OD

6-8 weeks

Standard of care

30 days


4545

X-TRA: endpoints

Primary endpoints:

• The percentage of subjects with complete resolution of left atrial

or left atrial appendage thrombus at the end of treatment


• Categories of thrombus outcome in subjects: resolved, reduced, unchanged, enlarged or new

• The composite number of stroke and non-central nervous system systemic embolism events

• The number of all bleeding events

Anticipated timelines: first patient visit: May 2013

last patient visit: Jul 2014


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Rivaroxaban: efficacia e sicurezza dei NAO · Dose totale giornaliera 120 mg * ... AF who are...

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