Nouveaux anticoagulants de la MTEV: encore du neuf
Dr Florence Parent
Service de Pneumologie et Soins Intensifs Hôpital Bicêtre, AP-‐HP
Inserm U999. Université Paris-‐Sud
DéclaraCon de liens d ’ intérêts
• Bayer (rivaroxaban)
• Boehringer (dabigatran)
• Pfizer (apixaban)
• Daiichi-‐Sankyo (edoxaban)
• Leo Pharma (Cnzaparine)
Rivaroxaban (Xarelto®):
AMM pour le traitement de la
TVP et de l ’ EP non grave
Les études Einstein
Randomized, open-label, event-driven, non inferiority study Non inferiority margin: 2.0
Predefined treatment period of 3, 6, or 12 months
15 mg bid
Confirmed DVT without symptomatic
PE N=3449
Rivaroxaban
Day 1 Day 21
Enoxaparin bid for at least 5 days + VKA INR 2.5 (INR range 2–3)
Confirmed PE
± symptomatic DVT
20 mg od
N=4833
30 -d ay p o st-s tu d y tr ea tm en t p er io d
Rivaroxaban
R
The Einstein Investigators NEJM 2010;363:2499–2510
The Einstein-PE Investigators NEJM 2012;366:1287–97
Rivaroxaban (Xarelto®):
Traitement de la TVP et de l ’ EP non grave
§ Inhibiteur spécifique direct du facteur Xa, par voie orale, sans surveillance biologique
§ Dose: 15 mg x 2 / jour, pendant 3 semaines, puis 20 mg / jour en 1 prise
§ Contre-‐indicaCon: insuffisance rénale sévère (Cl Creat < 15 mL/min)
§ Efficacité: non infériorité par rapport au traitement convenConnel (HBPM – AVK)
§ Saignements:
§ IdenCque pour l ’ ensemble des hémorragies
§ Moins d ’ hémorragies majeures
EINSTEIN PE: paCents
Rivaroxaban
(n=2419) Enoxaparine/AVK (n=2413)
Hommes, % 54.1 51.7
Age, moyenne, ans 57.9 57.5
Indice masse corporelle, moyenne, kg/m
228.3 28.4
Clairance crea=nine, %
<30 ml/min 0.2 <0.1
30–49 ml/min 8.6 7.9
50–79 ml/min 26.3 24.6
≥80 ml/min 64.3 67.0
Cancer ac=f, %
ATCD MTEV, % 4.7
18.8 4.5
20.3 Durée de traitement prévue, %
3 mois 5.3 5.1
6 mois 57.3 57.5
12 mois 37.4 37.5
Extension anatomique de l’EP, % Limitée (1 lobe, obstrucCon ≤ 25%) Intermédiaire
Extensive (mulC-‐lobaires, obstrucCon >25%)
12.8 57.5 24.7
12.4 59.0 23.9
ITT population
EINSTEIN PE: critère principal d ’ efficacité
ITT population 3.0 2.5 2.0 1.5 1.0
0.0 0.5
0 30 60 90 120 150 180 210 240 270 300 330 360
Number of pa=ents at risk
Rivaroxaban 2419 2350 2321 2303 2180 2167 2063 837 794 785 757 725 672 Enoxaparin/VKA 2413 2316 2295 2274 2155 2146 2050 835 787 772 746 722 675
Time to event (days)
Rivaroxaban N=2419
Enoxaparin/VKA N=2413
HR=1.12; p=0.0026 (non-inferiority)
C u m u la ti ve e ve n t ra te (% )
EINSTEIN PE: critère principal de tolérance:
saignements majeurs + cliniquement significaCfs
Rivaroxaban
n/N (%) Enoxaparin/VKA
n/N (%) HR (95% CI) p-‐value 249/2412 (10.3) 274/2405 (11.4) 0.90 (0.76–1.07)
p=0.23
Safety population
0 30 60 90 120 150 180 210 240 270 300 330 360 15
14
10 13 12 11 9 8 7 6 5 4 3 2 1 0
Number of pa=ents at risk
Rivaroxaban 2412 2183 2133 2024 1953 1913 1211 696 671 632 600 588 313 Enoxaparin/VKA 2405 2184 2115 1990 1923 1887 1092 687 660 620 589 574 251
Time to event (days)
Rivaroxaban N=2412
Enoxaparin/VKA N=2405
C u m u la ti ve e ve n t ra te (% )
Safety population 3.0 2.5 2.0 1.5 1.0
0.0 0.5
0 30 60 90 120 150 180 210 240 270 300 330 360
C u m u la ti ve e ve n t ra te (% )
Time to event (days)
Rivaroxaban N=2412
Enoxaparin/VKA N=2405
Number of pa=ents at risk
Rivaroxaban 2412 2281 2248 2156 2091 2063 1317 761 735 700 669 659 350 Enoxaparin/VKA 2405 2270 2224 2116 2063 2036 1176 746 719 680 658 642 278
EINSTEIN PE: saignements majeurs
Rivaroxaban
n/N (%) Enoxaparin/VKA
n/N (%) HR (95% CI) p-‐value 26/2412
(1.1) 52/2405
(2.2) 0.49 (0.31–0.79)
p=0.0032
Evènement Rivaroxaban Enoxaparine/AVK HR (95% CI)
n/N % n/N %
Récidive ETEV
Fragile 21/791 2.7 30/782 3.8 0.68
(0.39–1.18)
Non-‐fragile 65/3359 1.9 65/3349 1.9 0.98
(0.70–1.38)
Saignement majeur
Fragile 10/788 1.3 35/779 4.5 0.27
(0.13–0.54)
Non-‐fragile 30/3342 0.9 37/3337 1.1 0.80
(0.49–1.29)
EINSTEIN DVT et PE:
analyse poolée chez les paCents “fragiles*”
*Age >75 ans ou CrCl <50 ml/min ou poids ≤50 kg
Quels nouveaux anticoagulants oraux:
Dabigatran (Pradaxa®) Rivaroxaban (Xarelto®) PTH / PTG Dose: 75 ou 110 mg x 2
AMM: 03/2008
Disponibilité: 12/2008 ASMR: V
Dose: 10mg x 1 AMM: 09/2008
Disponibilité: 05/2009 ASMR: V
FA non valvulaire Dose: 110 ou 150 mg x 2 AMM: 08-‐2011
Disponibilité: 08/2012 ASMR: V
Dose: 20 mg x 1 (ou 15 mg/j) AMM: 12/2011
Disponibilité : 09/2012 ASMR: V
MTEV
-‐-‐-‐-‐-‐-‐-‐-‐ Dose: 15mg x 2/3sem, puis 20mgx1
AMM: 09-‐2012 ASMR: V
En cas d ’ insuffisance
rénale CI si clearance < 30 mL/min CI si clearance < 15 mL/min
AdaptaBon entre 15 et 50 mL/min
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
Total
(N=5649) France
(N=1318) Germany (N=1400) Italy
(N=1348) Spain
(N=686) UK (N=897)
Percentage of patients
acenocoumarol fluindione phenprocoumon warfarin
Figure 1: Types of Vitamin K antagonists
Figure 2: Sites of INR management
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
Total (N=7243)
France (N=1532)
Germany (N=1771)
Italy (N=1888)
Spain (N=858)
UK (N=1194)
Percentage of patients
Hospital
Anticoagulation centre Physician's office Self-measurement Other, e.g. biology lab
Figure 3: Time in therapeutic range
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
Total
(N=7243) France
(N=1532) Germany (N=1771) Italy
(N=1888) Spain
(N=858) UK (N=1194)
Percentage of patients
Adequate INR control
Suboptimal INR control
Unstable/high INRs according to physician’s judgement
INTRODUCTION/RATIONALE
• The profile of atrial fibrillation (AF) patients in Western Europe is well known, but few comparative data concerning management decisions in different parts of Europe are available.
• Different country specific practices exist with regard to the use of other Vitamin K antagonists (VKA) than warfarin.
• Also the sites where INR measurements are performed, vary across Europe.
• The PREFER in AF registry allows a comparison of the quality of INR control, using different types of VKAs as well as different sites of INR management.
METHODS
Design
• The PREFER in AF is a multi-national, multi-centre, prospective observational disease registry with the aim to gain detailed insight on the characteristics and management of AF patients with focus on prevention of thromboembolic events.
• The registry consists of one baseline visit and one follow-up visit after one year.
• Patients (pts) were enrolled from January 2012 to January 2013 and baseline data were collected in seven representative European countries: Austria, France, Germany, Italy, Spain, Switzerland, United Kingdom (UK).
• For regional comparisons, Austria, Switzerland, and Germany were combined into one pre-specified region.
Patients
• Pts were included if they were at least 18 years of age, gave written informed consent for participation in the registry, and had a history of AF documented by electrocardiography or by an implanted pacemaker or defibrillator within the preceding 12 months.
• No explicit exclusion criteria were defined to avoid biased selection of pts and achieve a cohort close to
“real-life”.
Statistical analysis
• Binary, categorical, and ordinal parameters were summarized by means of absolute and percentage numbers within the various categories.
• Numerical data were summarized by means of standard statistics.
Total France Germany Italy Spain UK
(N=7243) (N=1532) (N=1771) (N=1888) (N=858) (N=1194)
Age [years] (mean) 71.5 72.9 71.9 70.9 70.5 70.7
Male (%) 60.1 59.3 63.0 57.0 56.0 64.5
Height [cm] (mean) 169.2 169.1 171.7 167.3 165.5 171.5
Weight [kg] (mean) 80.3 78.3 84.0 76.2 76.9 86.5
Body Mass Index [kg/m2] (mean) 27.9 27.3 28.4 27.2 28.1 29.3
Table 1: Demographic data
Total France Germany Italy Spain UK
(N=7243) (N=1532) (N=1771) (N=1888) (N=858) (N=1194)
Hypertension (%) 72.0 63.8 81.9 75.3 72.7 62.1
Diabetes mellitus (%) 22.4 16.8 31.2 19.2 26.4 18.8
Obesity (%) 27.5 24.8 30.8 21.9 25.7 36.0
Coronary artery disease (%) 23.4 18.2 29.6 20.6 21.6 26.6
Prior stroke (%) 8.4 8.9 10.7 6.5 7.7 8.0
Heart failure (%) 21.3 18.2 28.4 19.4 24.4 15.4
CHA2DS2-VASc score (mean) 3.4 3.3 3.7 3.3 3.3 3.2
HAS-BLED score (mean) 2.0 1.9 2.1 2.1 2.0 2.0
Table 2: Risk factors
Total France Germany Italy Spain UK
(N=7243) (N=1532) (N=1771) (N=1888) (N=858) (N=1194)
Pts with rhythm control * (%) 50.7 60.7 44.1 59.2 41.8 39.5
Pts with adequate heart rate control
(HR 60-100), % 78.6 79.4 81.4 78.7 79.5 72.6
Pts with acceptable heart rate control
(HR 50-59 or 101-110), % 14.3 14.9 12.2 13.8 15.5 16.5
Pts without adequate heart rate control
(HR<50 or >110), % 7.1 5.7 6.4 7.5 5.1 11.0
Antiplatelet agents (AP), % 22.1 16.9 17.2 27.0 18.7 30.7
Vitamin K antagonists (VKA), % 78.0 86.0 79.1 71.4 80.0 75.1 Combination therapy (VKA + AP), % 9.9 10.1 7.7 8.8 10.3 14.7
Novel oral anticoagulants, % 6.1 6.0 11.6 0.3 11.2 3.7
No antithrombotic therapy, % 6.5 4.1 5.0 10.4 5.7 6.5
* Rhythm control defined as patients with cardioversion, ablation or antiarrhythmic drugs
Table 3: Rate vs rhythm control and anticoagulation
CONCLUSIONS
• Despite a relative homogeneity of AF profiles, the anticoagulation management remains different throughout these countries, mainly concerning the type of Vitamin K antagonists prescribed and the mode of INR surveillance.
• However this does not seem to affect the quality of anticoagulation, as estimated by three INRs at enrolment.
.
ACKNOWLEDGEMENTS
• We would like to thank all centres who participated in this registry and all patients who gave their consent to participate.
• Furthermore, we would like to thank Markus Schwertfeger for medical advice and Paul-Egbert Reimitz for statistical advice and programming (both employees of Daiichi Sankyo Europe).
ANTICOAGULATION MANAGEMENT IN ATRIAL FIBRILLATION: COUNTRY DIFFERENCES IN WESTERN EUROPE - DATA FROM THE PREFER IN AF REGISTRY
Jean-Yves Le Heuzey
1, Bettina Ammentorp
2, Harald Darius
3, Raffaele De Caterina
4, Richard John Schilling
5, Josef Schmitt
2, José Luis Zamorano
6, Paulus Kirchhof
7,81Cardiology and Arrhythmology, Georges Pompidou Hospital, René Descartes University, Paris, France; 2Daiichi Sankyo Europe, Munich, Germany; 3Vivantes Hospital Neukölln, Berlin, Germany; 4Institute of Cardiology G. d'Annunzio, University Chieti-Pescara, Italy; 5Barts and St Thomas Hospital, London, UK;
6Department of Cardiology, University Hospital Ramón y Cajal, Madrid, Spain; 7University of Birmingham Centre for Cardiovascular Sciences and SWBH NHS Trust, Birmingham, UK; 8Department of Cardiovascular Medicine, Hospital of the University of Münster, Germany
RESULTS
Patient population
• The PREFER in AF registry enrolled 7243 pts. The mean age was 71.5 years, varying from 70.5 (Spain) to 72.9 years (France). (Table 1)
• 72.0 % of pts had hypertension (from 62.1 % in UK to 81.9% in Germany), 22.4 % had diabetes (from 16.8 % in France to 31.2% in Germany).
• Obesity (BMI > 30 mg/kg) was observed in 27.5 % (from 21.9 % in Italy to 36.0 % in UK), and 23.4 % had coronary artery disease (from 18.2 % in France to 29.6 % in Germany).
• A previous ischemic stroke was observed in 8.4 % (from 6.5 % in Italy to 10.7 % in Germany), heart failure in 21.3 % (from 15.4 % in UK to 28.4% in Germany).
• The mean CHA2DS2-VASc score was 3.4 (from 3.2 in UK to 3.7 in Germany) and the mean HAS-BLED score was 2.0 (from 1.9 in France to 2.1 in Germany and Italy). (Table 2)
Therapeutic management
• A rhythm control strategy was chosen in 50.7% (from 39.5 % in UK to 60.7 % in France) whereas 78.6
% of patients were adequately rate-controlled (from 72.6 % in UK to 81.4 % in Germany).
• Despite this overall homogeneity, the anticoagulation management showed important discrepancies: the proportion of patients receiving Vitamin K antagonists was 86.0 % in France, 80.0 % in Spain, 79.1 % in Germany, 75.1 % in UK and 71.4% in Italy. (Table 3)
• The type of Vitamin K antagonists was very different: the most frequently prescribed VKA was warfarin in UK and Italy (74.9 % and 62.0 %, respectively); phenprocoumon in Germany (74.1 %),
acenocoumarol in Spain (67.3 %) and fluindione in France (61.8 %). (Figure 1)
• The sites of INR measurements varied considerably: In France INR measurements were predominantly done at biology labs (93.1 %), whereas in Germany the majority of tests was conducted at the physician’s office (83.2 %).
• Anticoagulation centres were the most frequently used sites for INR measurements in Italy (44.2 %), Spain (32.8 %) and UK (29.1 %). (Figure 2)
• The time in therapeutic range, estimated from the last three INR values prior to enrolment, was comparable in these different countries.
• Patients with adequate INR control, defined as 2 or 3 INR values in range, was seen in 72.1 % of cases (from 63.8 % in Spain to 79.2 % in Germany), but was overestimated by the physicians in almost all countries: unstable/high INRs according to physician’s judgment were reported only in 18.3 % of patients (from 9.8 % in Germany to 29.8 % in Spain). (Figure 3)
LE HEUZEY J.Y. et al. ESC 2013"
Le syndicat des jeunes biologistes médicaux «Crent la
sonneue d'alarme» en criCquant l'usage croissant de ces
NACO car «l'absence d'anCdote dis-‐po-‐nible fait de ces
molé-‐cules une bombe à retardement». Une mise en garde
très inquiétante que rejeue en bloc l'Agence du médicament
(ANSM). «Il n'y a aucun nouvel élément qui jusCfie une
alerte ou qui remeurait en cause le niveau de risque de ces
nouveaux médicaments» affirme le Dr Lozi Boudali, en
charge de ce type de médicament à l'ANSM.
Dabigatran :
Alerte Japonaise dans la FA (été 2011)
¢ Depuis l ’ autorisation au Japon en janvier 2011 dans la FA (Pradaxa 220 mg/j) : 6 décès par complication hémorragique ; 4 F et 2M, âgés (76 à 100 ans) ; petits poids : 4 patients < 45 kg.
¢ Dans un cas, le rôle du dabigatran est exclu car hémorragie digestive après relais par AVK.
¢ Délai < 3 semaines après l ’ introduction du Pradaxa®
¢ Facteurs de risque : 3 insuffisances rénales (dont deux Clairance créat < 30 ml/min = CI), 2 traitements concomitants par aspirine.
¢ Un cas d ’ hématome d ’ évolution défavorable en hémorragie digestive
malgré diminution de dose à 150 mg/j.
PRADAXA® et XARELTO ®
Suivi naConal de pharmacovigilance
Commission de suivi du bénéfice/risque des produits de santé -‐ ANSM 26 novembre 2013
P. Lainé-‐Cessac, CRPV d'Angers
A. Lillo-‐Le louët, CRPV HEGP
Historique du suivi naConal de Pharmacovigilance
*12/2008 : Pradaxa®
Chir Ortho
*05/2009 : Xarelto®
Chir Ortho
1 er suivi de PV CNPV 07/2010
*08/2012 : Pradaxa®
FA
*08-09/2012 : Xarelto®
FA, TVP, EP
2 ème suivi de PV
CTPV 02/2013 3 ème suivi de PV CTPV 11/2013
Tous les cas :
• chir ortho
Tous les cas :
• Indic Chir ortho
• Indic. Med
Cas graves :
• Indic Chir ortho
• Indic. Med
*Date de mise à disposiCon en France
Méthodologie commune du suivi
¢ Échanges laboratoires /CRPV tous les mois
¢ Recherche doublons
¢ Critères d'exclusion
¢ Réévaluation de tous les cas français graves issus de la notification spontanée, de la commercialisation au 31/08/2013
¢ Répartition des cas selon l ’ indication chirurgicale ou médicale.
¢ Définitions des hémorragies et des ETE majeurs similaires à celle des essais cliniques.
¢ Analyse des PSURs
¢ Recherche bibliographique
PGR
¢ Risque identifié : hémorragies
¢ Risques potentiels :
l Atteinte hépatique
l Anaphylaxie
¢ Risque théorique :
l SCA
¢ Interactions médicamenteuses (IAM)
¢ Description de la population traitée
¢ Autres points :
l Surdosage ( prise en charge )
l mésusage
l Abus
l Utilisation en pédiatrie
¢ Risque identifié : hémorragies
¢ Risques potentiels :
l Atteinte hépatique
l Atteinte pancréatique
l Atteinte rénale
¢ Études de cohorte observationnelle
l XAMOS
l XANTUS
l XALIA
¢ Études d'utilisation (UK, NL, DE)
¢ Informations manquantes
l Patients ClCr < 30 ml/mn
l Grossesse et allaitement
l Surdosage (prise en charge)
l IAM
PRADAXA XARELTO
DDJ= doses définies journalières
Rapport ansm , novembre 2013 (données Celtipharm)
DDJ= doses définies journalières
Rapport ansm , novembre 2013 (données Celtipharm)
Evolution trimestrielle des ventes des NACO par rapport aux ventes totales des anticoagulants oraux (janvier 2008 ‐ septembre 2013).
Rapport ansm , novembre 2013 (données Celtipharm)
AVK ≈70%
NACO ≈30%
Résultats globaux
• 1624 cas retenus
• 857 F, 755 H, 12 U
• âge moyen 77 ± 10 ans
• Indication conforme à AMM dans 97% des cas
• Effets inattendus : 34% des cas
• Décès 175 cas (11% des cas) :
– Âge: 80 ± 10 ans
– Indication: FA dans 61% des décès
– Hémorragies: 116 = 66% des décès
– ETE : 12,5% des décès
• 1566 cas retenus
• 814 F, 748 H, 4 U
• âge moyen 72 ± 14 ans
• Indication conforme à AMM dans 95% des cas
• Effets inattendus : 32% des cas
• Décès 127 cas (8% des cas) :
– Âge: 79 ans [43-94]
– Indication: médicale dans 77%
des décès
– Hémorragies: 82 = 65% des décès (49 HIC, 16 HD)
– ETE : 19% des décès
XARELTO
PRADAXA
Les hémorragies (hors décès)
¢ 802 cas (55% des cas hors décès)
¢ F 52,4% ; âge moyen 79 ans ± 10 ans
¢ Indication FA : 62%
¢ 211 associées à une anémie (26% des hémorragies)
¢ Localisation des hémorragies :
l Digestives : 48%
l intracrâniennes : 9%
¢ Hémorragies majeures dans 52% des cas
¢ Médicaments associés susceptibles d'interaction dans 26% des cas
¢ Fonction rénale initiale et poids très peu renseignés
¢ 809 cas (57% des cas hors décès)
¢ F 50% ; âge moyen 72 ans ±14 ans
¢ Indication médicale : 71%
¢ 164 associées à une anémie (20% des hémorragies)
¢ Localisation des hémorragies :
l Digestives : 29 %
l intracrâniennes : 10%
¢ Hémorragies majeures dans 42% des cas
¢ Médicaments associés susceptibles d'interaction dans 23% des cas
¢ Fonction rénale initiale et poids très peu renseignés
PRADAXA XARELTO
Répartition des Effets indésirables (EI) retenus (hors décès)
53%
21%
1%
6%
4%
2% 4% 1%2% 2% 4%
EI hémorragiques ETE
EI CV autres EI hématologiques EI cutanés
digestifs
EI hépatobiliaires EI généraux EI neuroΨ EI rénaux EI divers
