en ‘vraie vie’ dans la fa : un nouvel éclairage sur les...
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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
Rivaroxaban Warfarin
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
Rivaroxaban Warfarin
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
Event Rates are per 100 patient-years
Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations
Primary Safety Outcomes
Rivaroxaban Warfarin
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
Event Rates are per 100 patient-years
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
Camm AJ et al, Eur Heart J. 2015;online.
Camm AJ et al, Eur Heart J. 2015;online.
Camm AJ et al, Eur Heart J. 2015;online.
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
Camm AJ et al, Eur Heart J. 2015;online.
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
Camm AJ et al, Eur Heart J. 2015;online.
Outcomes as a function of CHADS2
Camm AJ et al, Eur Heart J. 2015;online.
Outcomes as a function of CHADS2-VASc
Camm AJ et al, Eur Heart J. 2015;online.
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
Camm AJ et al, Eur Heart J. 2015;online.
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;
Camm AJ et al, Eur Heart J. 2015;online.
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