en ‘vraie vie’ dans la FA : Un nouvel éclairage sur les AODsamcar.ma/ressources/att/journees/2016/Cottin AOD... · en ‘vraie vie’ dans la FA : Un nouvel éclairage sur les

Les premières données prospectives

en ‘vraie vie’ dans la FA :

Un nouvel éclairage sur les AODs

Dr Y Cottin

Dijon

Conflits d’intérêt

Astra-Zeneca, BMS, MSD, Novartis,

Pfizer, Bayer, Servier,

CRAM, AFSSAPS, ARH

Région de Bourgogne

Clos Vougeot

Kenneth W. Mahaffey, MD and Keith AA Fox, MB ChB

on behalf of the ROCKET AF Investigators

Rivaroxaban Once-daily oral direct factor Xa inhibition

Compared with vitamin K antagonism for prevention

of stroke and Embolism Trial in Atrial Fibrillation

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*

Statistical Methodologies

– Sample Size

• Warfarin event rate ~2.3

• Type 1 error 0.05 (2-sided)

• 405 events; >95% power

• ~14,000 patients

Primary Efficacy Evaluation: Stroke or non-CNS Embolism

Non-Inferiority: Protocol Compliant on treatment

Superiority: On Treatment and then by Intention-to-Treat

– Primary Safety Evaluation: Major or non-Major Clinically

Relevant Bleeding

1.0 1.46

Superiority

Non-inferiority

Inferiority

Rivaroxaban

Better

Warfarin

Better

Study Conduct


Randomized, n

Lost to Follow-up, n

Premature Discontinuation, n (%)

Withdrew Consent, n

Median (25th, 75th) Exposure (days)

Median (25th, 75th) Follow-up (days)

7131

18

1693 (23.9%)

626

589 (396, 805)

706 (522, 884)

7133

18

1589 (22.4%)

620

593 (404, 810)

708 (518, 886)

Primary Efficacy Outcome Stroke 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 e

ven

t ra

te (

%)

Rivaroxaban

Rivaroxaba

n

Warfarin

Event

Rate 1.71 2.16


Event

Rate

Event

Rate

HR

(95% CI) P-value

On

Treatment N= 14,143

1.70 2.15 0.79

(0.65,0.95) 0.015

ITT N= 14,171

2.12 2.42 0.88

(0.74,1.03) 0.117

Rivaroxaban

better

Warfarin

better

Primary Efficacy Outcome Stroke and non-CNS Embolism


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

Primary Safety Outcomes


Event Rate Event Rate HR

(95% CI)

P-

value

Major and non-major

Clinically Relevant 14.91 14.52

1.03 (0.96,

1.11) 0.442

Major 3.60 3.45 1.04 (0.90,

1.20) 0.576

Non-major Clinically

Relevant 11.80 11.37

1.04 (0.96,

1.13) 0.345


Based on Safety on Treatment Population

Cohortes Big Data Etude prospective

non interventionnelle

Exemple

Dresden NACORA XANTUS

Etude de Référence

Non

Non ROCKET AF

Prospective/Rétrospective Prospective Rétrospective Prospective

Inclusions Régionale Nationale Internationale

Critères inclusion Patient sous

traitement

Patient sous

traitement Intention de traiter

Critères de jugement Issu du suivi Issu des bigs datas

;Ex hospitalisation Issu du design

Validation du critère de

jugement non non Oui comité d’adjudication

Statistiques Descriptive Descriptive Score de propension

Drug persistence with rivaroxaban therapy in atrial

fibrillation patients-results from the Dresden non-

interventional oral anticoagulation registry

Beyer-Westendorf J, et al. Europace. 2015;17(4):530-8.

Beyer-Westendorf J, et al. Blood. 2014;124:955-62.

Rates, management, and outcome of rivaroxaban bleeding

in daily care: results from the Dresden NOAC registry.

ETUDE NACORA

Étude ‘en vie réelle’ du bénéfice/risque à court terme des nouveaux anticoagulants oraux (dabigatran, rivaroxaban) chez les patients

débutant un traitement et non précédemment traités par des antivitamines K

• Étude du projet NACORA (nouveaux anticoagulants oraux et risques associés) • Département des Études en Santé Publique,

• Caisse Nationale d’Assurance Maladie des Travailleurs Salariés (CNAMTS)

• en collaboration avec le Pole Epidémiologie des Produits de Santé de l’Agence Nationale de Sécurité des Médicaments et des produits de santé (ANSM)

• Rapport du 23 juin 2014

NACORA – étude CNAM

Patients:

71589 nouveaux utilisateurs de AOD et d’AVK (pat. ’naïfs’) – quelle que soit l’indication (FA ou TVP/EP)

Suivi: 90 premiers jours de traitement

2ème semestre 2012

Objectif principal :

• Rrisque d’hémorragie majeure

Objectifs secondaires:

• Risque d’AVC/ES et IDM - chez les patients FA

• Mortalité totale à 30 jours

Caractéristiques des patients :

différences….

Résultats:

Objectif principal: Hémorragies majeures: réduction statistiquement significative sous AOD versus AVK

•

Résultats:

Objectif secondaire: Hémorragies majeures ou décès toute cause:

réduction statistiquement significative sous AOD versus AVK

Résultats:

Objectif secondaire: AVC ischémique / ES: pas de différence significative entre AOD et AVK

Cohortes Big Data Etude prospective

non interventionnelle

Exemple

Dresden NACORA XANTUS

Etude de Référence

Non

Non ROCKET AF

Prospective/Rétrospective Prospective Rétrospective Prospective

Inclusions Régionale Nationale Internationale

Critères inclusion Patient sous

traitement

Patient sous

traitement Intention de traiter

Critères de jugement Issu du suivi Issu des bigs datas

;Ex hospitalisation Issu du design

Validation du critère de

jugement non non Oui comité d’adjudication

Statistiques Descriptive Descriptive Score de propension

~ 1430 patients recruited in France (63 centers)

First International, Prospective Observational Study of a Novel OAC for

Stroke Prevention in a Broad NVAF Patient Population

6,784 adult NVAF patients newly started on once-daily Xarelto®

Enrolled from June 2012 until December 2013

Over 311 study centres in Europe, Canada, and Israel

Patients were followed up for 1 year at ~3-months intervals or

for at least 30 days after permanent treatment discontinuation1

To collect real-life data on adverse events in patients with non-

valvular AF treated with rivaroxaban to determine its safety profile

across the broad range of patient risk profiles encountered in

routine clinical practice

• Primary outcomes : major bleeding (ISTH definition), all-cause

mortality, any other adverse events

Final visit:

1 year#

Data collection at initial

visit, hospital discharge

(if applicable) and

quarterly*

Population: Adult patients with non-valvular AF receiving rivaroxaban for stroke/ non-CNS systemic embolism prevention, who had provided written informed consent

Rivaroxaban; treatment duration

and dose at physician’s discretion

Prospective, single-arm, observational, non-interventional phase IV study

Statistical analyses were descriptive and exploratory in nature

Study Objective and Design

Prospective, single-arm, observational, non-interventional phase IV study

Statistical analyses were descriptive and exploratory in nature

Primary and Secondary Outcomes

Camm AJ et al, Vasc Health Risk Manag 2014;10:425–434

Primary outcomes

Major bleeding (ISTH definition)

All-cause mortality

Any other AEs

Any other serious AEs

Secondary outcomes

Symptomatic thromboembolic

events

Non-major bleeding events

Any bleeding event that does

not meet the criteria for a

major haemorrhage

AEs and serious AEs across

risk scores

AEs and serious AEs in important

subgroups

Other outcomes collected

included:

Patient treatment satisfaction

using standardized

questionnaires

Persistence with therapy

Healthcare resource use

Details of interventions and how

they were managed

Concomitant medication use

Reasons for

switching/interrupting

rivaroxaban therapy

Camm AJ et al, Vasc Health Risk Manag 2014;10:425–434

Screened

(N=10,934)

1 patient

Did not take any rivaroxaban (n=1)

Enrolled

(N=6785)

Safety population

(N=6784)

Another dose

(n=35)#

Rivaroxaban 20 mg

(n=5336)

Rivaroxaban 15 mg

(n=1410)

4149 patients excluded*

Patient decision (n=1222)

Administrative reason (n=456)

Availability of drug (n=18)

Medical guidelines (n=399)

Price of drug (n=473)

Medical reasons (n=442)

Internal hospital guidelines (n=30)

Type of health insurance (n=183)

Other (n=1454)

Primary analysis population:

defined as all patients who

had taken at least one dose

of rivaroxaban

Major events, specifically

major bleeding, stroke, SE,

TIA and MI, adjudicated

centrally by an Adjudication

Committee blinded to

individual patient data

Patient Disposition

Camm AJ et al, Eur Heart J. 2015;online.

Baseline Demographics and Clinical Characteristics

Rivaroxaban

(N=6784)

Age (years)

Mean±SD 71.5±10.0

Age <65, n (%) 1478 (21.8)

Age ≥65–≤75, n (%) 2782 (41.0)

Age >75, n (%) 2524 (37.2)

Gender (male), n (%) 4016 (59.2)

Weight (kg), mean±SD 83.0±17.3

BMI (kg/m2), mean±SD 28.3±5.0

CHADS2 score, mean±SD 2.0±1.3

CHA2DS2-VASc score, mean±SD 3.4±1.7

AF, n (%)

First diagnosed 1253 (18.5)

Paroxysmal 2757 (40.6)

Persistent 923 (13.6)

Permanent 1835 (27.0)

Missing 16 (0.2)

Rivaroxaban

(N=6784)

VKA experienced 3089 (45.5)

VKA naïve 3695 (54.5)

Creatinine clearance, n (%)

<15 ml/min 20 (0.3)

≥15–<30 ml/min 75 (1.1)

≥30–<50 ml/min 545 (8.0)

≥50–≤80 ml/min 2354 (34.7)

>80 ml/min 1458 (21.5)

Missing 2332 (34.4)

Co-morbidities, n (%)

Hypertension 5065 (74.7)

Diabetes mellitus 1333 (19.6)

Prior stroke/non-CNS SE/TIA 1291 (19.0)

Congestive HF 1265 (18.6)

Prior MI 688 (10.1)

Hospitalization at baseline, n (%) 1226 (18.1)

Event-Free Rate (Kaplan–Meier) for

Treatment-Emergent Primary Outcomes

In total, 6522 (96.1%) patients did not experience any of the outcomes

of treatment-emergent all-cause death, major bleeding or stroke/SE




Rivaroxaban (N=6784)

Incidence

proportion, n (%)

Incidence rate,

%/year (95% CI)*

Major bleeding 128 (1.9) 2.1 (1.8–2.5)

Fatal 12 (0.2) 0.2 (0.1–0.3)

Critical organ bleeding 43 (0.6) 0.7 (0.5–0.9)

Intracranial haemorrhage 26 (0.4) 0.4 (0.3–0.6)

Mucosal bleeding# 60 (0.9) 1.0 (0.7–1.3)

Gastrointestinal 52 (0.8) 0.9 (0.6–1.1)

Haemoglobin decrease ≥2 g/dl‡ 52 (0.8) 0.9 (0.6–1.1)

Transfusion of ≥2 units of packed RBCs or

whole blood‡ 53 (0.8) 0.9 (0.6–1.1)

Non-major bleeding events 878 (12.9) 15.4 (14.4–16.5)

Treatment-Emergent Bleeding Events


Adjudicated Causes of Death

Number of patients (N=118*),

n (%)

Cardiovascular 49 (41.5)

Cardiac decompensation, heart failure 24 (20.3)

Sudden or unwitnessed death 14 (11.9)

MI 6 (5.1)

Non-haemorrhagic stroke 4 (3.4)

Dysrhythmia 1 (0.8)

Cancer 23 (19.5)

Other 16 (13.6)

Bleeding 12 (10.2)

Extracranial haemorrhage 5 (4.2)

Intracranial bleeding 7 (5.9)

Infectious disease 10 (8.5)

Unexplained 9 (7.6)

1

2

3

4


Outcomes as a function of CHADS2


Outcomes as a function of CHADS2-VASc


1,7

3,6

1,91,7

0,5

2,0

0,8

2,11,9

0,7

0,4

0,9

0,0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

4,0

Stroke/SE Major

bleeding

Death All strokes ICH Major GI

bleeding

Inci

de

nce

rat

e

Eve

nt

pe

r 1

00

pat

ien

t-ye

ars

ROCKET AF XANTUS

Comparison of Main Outcomes:

XANTUS versus ROCKET AF

AF Patients in ROCKET AF Had a Higher Risk of

Stroke than Patients in Other Phase III Trials

CHADS2 score patient distribution

ENGAGE AF4

edoxaban

52%

48%

ROCKET AF1

rivaroxaban

13%

87%

≤1 2 3–6

ARISTOTLE3

apixaban

36% 34%

30%

RE-LY2

dabigatran

32%

32%

36%

CHADS2 score

Mean CHADS2 score

41%

30%

29%

XANTUS5

Rivaroxaban

1. Patel MR et al, N Engl J Med 2011;365:883–891; 2. Connolly SJ et al, N Engl J Med 2009;361:1139–1151;

3. Granger CB et al, N Engl J Med 2011;365:981–992; 4. Giugliano RP et al, N Engl J Med 2013;369:2093–

2104;5. Camm AJ et al, Eur Heart J. 2015;online.

3.5 2.8 2.1 2.1 2.0


Outcomes in FANV patients with

similar CHADS2 score (CHADS2 ~ 2)

Beyer-Westendorf J et al. Europace. 2015; 17(4):530–538.

Drug persistence with rivaroxaban therapy in atrial

fibrillation patients-results from the Dresden non-

interventional oral anticoagulation registry.

.

Persistence

80% persistence rate over the period of 1 year 1

This finding coincided with 5096 (75.1%) patients reporting to their

physicians that they were ‘very satisfied’ or ‘satisfied’ with their

treatment 1

Consistent with the high persistence of Xarelto observed in other real-

world studies 2– 4

Higher persistence rate compared to VKA 2,3

80% Treatment Persistence with Once-Daily Xarelto

1. Camm AJ et al, Eur Heart J. 2015;online;

2. Laliberte F et al. Curr Med Res Opin. 2014; 30(7):1317–1325;

3. Nelson WW et al. Curr Med Res Opin. 2014; 30(12):2461–2469;

4. Beyer-Westendorf J et al. Europace. 2015; 17(4):530–538;


Conclusions

1. XANTUS is the first large prospective study that describes the use of

rivaroxaban in a broad patient population with non-valvular AF

2. Patients in XANTUS were at lower overall risk than those in the

rivaroxaban phase III ROCKET AF clinical trial

3. The rates of major bleeding and stroke with rivaroxaban were low in

routine clinical practice

4. Rivaroxaban once-daily in real world is associated with higher patient

persistence compared with warfarin (and dabigatran)

5. The net clinical benefit with rivaroxaban in a real world population

appeared to be greater than that with warfarin treatment according to a

modelling analysis

Documents

en ‘vraie vie’ dans la FA : Un nouvel éclairage sur les AODsamcar.ma/ressources/att/journees/2016/Cottin AOD... · en ‘vraie vie’ dans la FA : Un nouvel éclairage sur les