AOD en pratique Des études randomisées à la pratique Dr D Coisne ds/dt>0

TTR: Time on Therapeutic Range (2 to 3)

Les AOD

AOD FA Mal thromboembolique Association AAP Etude randomisée, registres, meta-analyses, recommandations Mal thromboembolique Phase aigue, traitement au long cours Association AAP Situations particulières ou la vrai vie Age extrêmes Surpoids Ins rénale Cancer Relais AC Cardioversion Phase aigue AVC …..

Dabigatran Rivaroxaban Apixaban Edoxaban

Ruff Lancet Mars 2014 AVC (ischémique, hémorragique) , Acc embolique périphérique -19% AVC+AEP:

Saignements majeurs Lancet Mars 2014 Transfusion de 2 CG, baisse de Hb > 2 g/l Saignement: intracranial, intraoculaire, intra-articulaire, retropéritoneal, gastrointéstinal) Saignement fatal. Saignements majeurs

Net clinical benefit associe: AVC ischémique, Embol systémique, IDM, AVC hémorragique, Hémorragies majeures, et Mortalité toute cause

Management of anticoagulation in patients with non-valvular atrial fibrillation in general practice in UK: Essra Ridha ESC 2015 London

AOD et maladie thrombo embolique

Traitement au long cours TVP/EP

C Becattini for the WARFASA study Randomisée TVP sans cause retrouvée De 6 à 18 mois de TTT Aspirine 100mg vs placébo

Taux de récidive: 6.6% vs. 11.2% par an Venous thromboembolism recurred in 28 of the 205 patients who received aspirin and in 43 of the 197 patients who received placebo (6.6% vs. 11.2% per year; hazard ratio, 0.58; 95% confidence interval [CI], 0.36 to 0.93) Taux de récidive: 6.6% vs. 11.2% par an

Trials : NACO and VTE/PE Extended period

Major Bleeding at 1 year: Apixaban 2,5*2 : 3%

TVP ou EP sans facteur de risque majeur Récidive de TVP ou EP peut être estimée à 10% par an lors des premières années Effet positif de l’aspirine sur la récidive de TVP Dabigatran à 150 mg*2 non inférieur à Warfarine. Taux moyen de récidive: 1% à 12 mois. Effet significatif de l’apixaban 2,5 X 2 , sans sur-risque de saignement majeur. Durée du Traitement ??? Critères d’inclusion pour le traitement au long cours?

Unprovoked VTE/PE

REVERSE II trial

AOD et antiaggregants D Coisne

Risque hémorragique en cas d’ACFA Hansen, Arch Intern Med 2010 Naco+Asp vs NACO = + 60 % bleeding risk

Events rate per Year

Events rate per Year

Les patients associant une FA et une maladie vasculaire stable (ex : sans événement aiguë ou de revascularisation > 12 mois, que ce soit pour une maladie coronarienne ou périphérique) peuvent être pris en charge par des anticoagulants oraux seuls (dose ajustée d’AVK ou AOD) Chez ses patients stables il n’est pas nécessaire d’associer de l’aspirine Peut augmenter le risque de saignements majeurs incluant les hémorragies intracrâniennes Camm AJ, et coll. Eur Heart J 2012;33:2719-47. Eikelboom JW, et al. Circulation 2011;123:2363-72.

ESC guidelines Diabetes 2013 Thus, in the most up-to-date meta-analysis, which includes three trials conducted specifically in patients withDMand six other trials in which such patients represent a subgroup within a broader population, aspirin was found to be associated with a non-significant 9% decrease in the risk of coronary events (RR 0.91; 95% CI 0.79–1.05) and a nonsignificant 15% reduction in the risk of stroke (RR 0.85; 95% CI 0.66–1.11).264 It should be emphasized that the total number of patients with DM enrolled in these nine trials was 11 787, with 10-year extrapolated coronary event rates ranging from as low as 2.5% to as high as 33.5%.264 aspirin was found to be associated with a non-significant 9% decrease in the risk of coronary events (RR 0.91; 95% CI 0.79–1.05) and a nonsignificant 15% reduction in the risk of stroke (RR 0.85; 95% CI 0.66–1.11

AOD et patients extrêmes

Patients fragiles/ patients extrêmes Ages extrêmes Ins rénale Associations thérapeutiques Poids extrêmes/Obésité FA Cancer , TVP et cancer Naco and phase aigue d’AVC Grossesse/allaitement TIH, AC circulants, Thrombopénie …..

Effet Age Mais…Sous utilisation majeure des AVK en fonction de l’âge

71 63 76

Apixaban vs Warfarin in Patients <80 vs ≥80 Years* No. of Events (%/yr) HR (95% CI) P interaction Apixaban Warfarin Stroke or Systemic Embolism 0.91 Age <80 yrs 179 (1.23) 225 (1.55) 0.79 (0.65–0.96) Age ≥80 yrs 33 (1.53) 40 (1.90) 0.81 (0.51–1.29) Major Bleeding 0.74 260 (1.93) 366 (2.78) 0.70 (0.60–0.82) 67 (3.55) 96 (5.41) 0.66 (0.48–0.90) All Bleeding 0.83 1964 (17.0) 2558 (24.4) 0.71 (0.67–0.76) 392 (26.4) 502 (37.4) 0.73 (0.64–0.83) Intracranial Haemorrhage 0.67 43 (0.32) 98 (0.73) 0.43 (0.30–0.62) 9 (0.47) 24 (1.32) 0.36 (0.17–0.77) All-Cause Mortality 0.73 452 (3.03) 507 (3.42) 0.88 (0.78–1.00) 151 (6.86) 162 (7.44) 0.93 (0.74–1.16) 0.25 0.5 1 2 Consistent with the overall trial results, apixaban was more effective than warfarin in reducing the risk of stroke or SE, major bleeding, all bleeding, ICH, and all-cause mortality in patients <80 and ≥80 years of age (all Pinteraction >0.05). *N=2654 CI, confidence interval HR, hazard ratio ICH, intracranial haemorrhage SE, systemic embolism Apixaban Better Warfarin Better Adapted from Halvorsen S, et al. Presented at: ACC 2013; March 9–11 Abstract: J Am Coll Cardiol 2013;61(10 suppl). Presentation 914-4 Halvorsen S, Wallentin L, Yang H, et al. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation. Oral presentation at: Joint Session of the Heart Rhythm Society and the American College of Cardiology; March 9–11, 2013; San Francisco, CA. Abstract published in: J Am Coll Cardiol. 2013;61(10 suppl). Presentation 914-4.

ARISTOTLE (apixaban) AVC ou embolie systémique et hémorragies majeures selon l’estimation de la fonction rénale par Cokcroft Hohnloser SH et al. European Heart Journal 1012.

Cas clinique Mme Ber 135Kg pour 170cm, BMI 46,7Kg/m2 50 ans DNID non compliqué HTA: Aprovel 300, Zanidip 10, PA 138/85 Bilan pré op de chirurgie bariatrique ECG . FA permanente. Notion de palpitation depuis 1 mois Biologie. Hb: 13.5 g/dl, Cl Cr: 95 ml/mn Echo FE normale à 65%, VG non dilaté, non hypertrophié, Flux Doppler normaux, VD non dilaté pas d’arguments pour une HTAP. Vol OG. 25 ml/m2 Une restauration du rythme sinusal est envisagée. Quid du traitement anticoagulant?

AOD et obésité Dabigatran Rivaroxaban Apixaban Edoxaban -20 % de concentration si poids > 100 KG mais pas de modif nécessaire en clinique Rivaroxaban Phase 2: pour un poids > 120 Kg (n=12; mean 132Kg, BMI: 43Kg/m2), pas de modification significative (Kubitza J Clin Pharma 2007) Rocket: faible proportion d’obèse. Pas de modif de dose Apixaban Si poids > 120Kg, réduction de 29% AuC mais ne semble pas être cliniquement significative (Upreti Br J Pharma 2013. Aristotle , pas d’adaptation de dose mais « faible » cohorte de surpoids (médian 82 Kg IQR 70-96) Edoxaban ?

AOD et obésité Pharmacocinétique Pas de modification apriori de l’absorption (mais quid de l’absorption post chirurgie bariatrique) Vol de distribution augmenté Débit de filtration glomérulaire et flux sanguin rénal augmenté chez l’obèse non diabétique Cmax . Auc réduits

Médian 82kg. Inter quartile Range 70-96 Body mass index and outcomes with apixaban versus warfarin in patients with atrial fibrillation in the ARISTOTLE trial Sandhu RK et al. Poster presentation at ACC March 2015; San Diego, CA , USA. Poster 1270M-07 Médian 82kg. Inter quartile Range 70-96 BMI category P Value* Characteristics < 25 kg/m2 (n=4246) 25.0-29.9 kg/m2 (n=6702) ≥ 30 kg/m2 (n=7159) Age (years) mean (SD) 71.2 (10.2) 70.1 (9.3) 66.8 (9.2) <.0001 CrCL ml/min (SD) 58.2 (19.8) 72.5 (22.8) 98.0 (35.7) <.0001 Beta Blocker 2361 (55.6) 4220 (63.0) 4849 (67.7) <.0001 ACE inhibitor/ARB 2582 (60.8) 4676 (69.8) 5510 (77.0) Lipid Lowering agent 1564 (36.8) 3001 (44.8) 3587 (50.1)

One Year Event Rates for Continuous BMI According to Study Treatment Médian 82kg. Inter quartile Range 70-96 All-cause mortality Composite Endpoint Stroke or Systemic Embolism Major Bleeding Nb of patient BMI> 40 Kg/m2? Obesity paradox? BMI – body mass index

Cardioversion? Nagarakanti R et al. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation 2011;123:131–6 RELY J.P. Piccini, S.R. Stevens, Y. Lokhnygina, et al., Outcomes after cardioversion and atrial fibrillation ablation in patients treatedwith rivaroxaban andwarfarin in the ROCKET AF trial, J. Am. Coll. Cardiol. 61 (2013) 1998–2006. G. Flaker, R.D. Lopes, S.M. Al-Khatib, et al., Efficacy and safety of apixaban in patients after cardioversion for atrial fibrillation: insights from the ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) J. Am. Coll. Cardiol. 63 (2014) 1082–1087. R. Cappato, M.D. Ezekowitz, A.L. Klein, et al., Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation, Eur. Heart J. 35 (2014) 3346–3355. X Vert TRIAL A Plitt Cardioversion of atrial fibrillation in ENGAGE AF TIMI 48. Clin Cardiol Fev 2016

Efficacy and safety of direct oral anticoagulants in patients undergoing cardioversion for atrial fibrillation: A systematic review and meta-analysis of the literature☆ n=2765 AOD AVK Embols (%) 0,41 0,61 Décès(%) 0,51 0,81 Saignements majeurs (%) 0,6 Francesco Dentali Int J Cardiol 2015

Niveau d’anticoagulation Relais AVK/ »héparine » et chirurgie programmée Chirurgie Niveau d’anticoagulation J-5 J-2 J+2 J+5

Stratégies de relais par « Heparine »

Embols Periprocedural Heparin Bridging in Patients Receiving Vitamin K Antagonists Systematic Review and Meta-Analysis of Bleeding and Thromboembolic Rates Deborah Siegal, MD, MSc; Jovana Yudin, MD, BSc; Embols

Saignement Periprocedural Heparin Bridging in Patients Receiving Vitamin K Antagonists Systematic Review and Meta-Analysis of Bleeding and Thromboembolic Rates Deborah Siegal, MD, MSc; Jovana Yudin, MD, BSc; Saignement

BRIDGE Trial NEJM 27 Oct 2015 N:1884

BRIDGE Trial NEJM 27 Oct 2015 Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had an elective surgery or procedure Substudy of the RE-LY trial Online Supplementary Material J. D. Douketis (1), J. S. Healey (1, 2), M. Brueckmann (3, 4), J. W. Eikelboom (1, 2), M. D. Ezekowitz (5), M. Fraessdorf (3), H. Noack (3), J. Oldgren (6), P. Reilly (7), A. C. Spyropoulos (8), L. Wallentin (6), S. J. Connolly (1, 2) (1) Department of Medicine, McMaster University, Hamilton, Canada; (2) Population Health Research Institute, McMaster University, Hamilton, Canada; (3) Boehringer Ingelheim Pharma GmbH & Co, Ingelheim am Rhein, Germany; (4) Medical Faculty Mannheim of the University of Heidelberg, Germany; (5) Jefferson Medical College, Wynnewood, Pennsylvania, USA; (6) Department of Medical Sciences, Cardiology, Uppsala Clinical Research Centre, Uppsala University, Sweden; (7) Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conneticut, USA; (8) North Shore-Long Island Jewish Health System, Manhasset, New York, USA Keywords surgery, warfarin, dabigatran, Bridging anticoagulation Summary In patients with atrial fibrillation (AF) who require interruption of dabigatran or warfarin for an elective surgery/procedure, the risks and benefits of perioperative bridging anticoagulation is uncertain.We accessed the database from RE-LY, a randomised trial comparing dabigatran with warfarin for stroke prevention in AF, to assess the potential benefits and risks of bridging. In patients who had a first interruption of dabigatran or warfarin for an elective surgery/procedure, we compared the risk for major bleeding (MB), stroke or systemic embolism (SSE) and any thromboembolism (TE) in patients who were bridged or not bridged during the period of seven days before until 30 days after surgery/procedure. We used multivariable Cox regression to adjust for potential confounders.Bridging was used more during warfarin interruption than dabigatran interruption (27.5 % vs 15.4 %; p< 0.001). With dabigatran interruption, bridged patients had more MB (6.5 % vs 1.8 %, p< 0.001) than those not bridged but bridged and not bridged groups did not differ for any TE (1.2 % vs 0.6 %, p=0.16) and SSE (0.5 % vs 0.3 %, p=0.46). With warfarin interruption, bridged patients had more MB (6.8 % vs 1.6 %, p< 0.001) and any TE (1.8 % vs 0.3 %, p=0.007) than those not bridged but bridged and not bridged groups did not differ for SSE (0.5 % vs 0.2 %, p=0.321). In conclusion, in patients who interrupted dabigatran or warfarin for a surgery/ procedure in the RE-LY trial, use of bridging anticoagulation appeared to increase the risk for major bleeding irrespective of dabigatran or warfarin interruption. <div class="schattauerManuscriptDoi schattauerManuscriptBlock"> <h3>DOI</h3> http://dx.doi.org/10.1160/TH14-04-0305 </div> // [PDF] [Pay per view] <a href="###LINK_MANUSCRIPT_PAYPERVIEW2###" target="_blank" onclick="return schattauerPaymentPopup(this.href);">[Pay per view]</a> [Add to basket] [Export citation] La stratégie placébo est non inférieure pour les embols mais supérieure pour les saignements Confirmation de ces donnée dans l’étude Rely (Dabigatran) J. D. Douketis

Dabigatran Rivaroxaban Apixaban Dernière prise de NOAC avant une chirurgie élective fonction de la ClCr, de la molécule et du type de chirurgie Dabigatran Rivaroxaban Apixaban Faible risque Haut risque ClCr>80 >24h >48 ClCr <80 >50 >36 >72 CLcr >30 <50 >96 ClCr <30 > 15 Non indIqué ClCr<15

Pas d’arrêt! Faible risque Haut risque

Relais en pratique Relais AVK/ NACO: première prise de NACO dès que l’INR<2 Reprise NACO en Post op: ( pic d’activité 4 à 6 h) fonction du type de chirurgie. Chirurgie à risque moyen: reprise le soir de l’intervention Chirurgie à haut risque: reprise le lendemain

Cas clinique Mr Fur… 73 ans asymptomatique ATCD de néoplasie de la prostate en cours de bilan Découverte d’une manière fortuite d’un EP sous segmentaire sans retentissement cardiologique Option thérapeutiques 1 Traité par HBPM pour l’EP (Reco ESC IIa) 2 Hormonothérapie pour le K de la prostate Vu en consultation à 6 mois. Va bien toujours sous HBPM PSA/50 , dernier dosage de PSA : 25 Quid de la poursuite de l’anticoagulation?

Actively recruiting in the US VTE Treatment Cancer: Objective Objective This randomized phase III trial studies the safety of and compares apixaban and dalteparin in reducing blood clots in patients with cancer-related venous thromboembolism. Design A Prospective, randomized, open –blinded endpoint (PROBE) superiority study (6 months) evaluating the safety of apixaban and dalteparin for the treatment of VTE in patients with cancer. N= 315 (estimated) Estimated study completion date: December 2020 Actively recruiting in the US Sponsored by Academic and Community Cancer Research United in collaboration with the National Cancer Institute and BMS/Pfizer; NCT 02585713

6 month follow-up period VTE Treatment Cancer: design PROBE Superiority Study (6 months ; Randomized, Open Label) Select Patient Eligibility Age ≥ 18 Confirmed acute lower or upper extremity* DVT, PE, splanchnic± or cerebral vein thrombosis Active cancer R Apixaban BID Lower Dose Apixaban BID Dalteparin Daily Lower Dose Dalteparin Daily 6 month follow-up period Day 1 Day 30 Day 7 SUPERIORITY DESIGN Primary endpoint: Major bleeding events which occurred during treatment or within 7 days of treatment discontinuation (on treatment analysis) Secondary endpoint(s): Major or CRNM bleeding events which occurred during treatment or within 7 days of treatment discontinuation (on treatment analysis); the time to the first event of the composite DVT/PE outcome *jugular, innominate, subclavian, axillary, brachial) ±hepatic, portal, splenic, mesenteric, renal, gonadal Sponsored by Academic and Community Cancer Research United in collaboration with the National Cancer Institute and BMS/Pfizer; NCT 02585713

TVP/EP et cancer au delà des 3 /6 mois ??? ESC 2008 Questions. Cancer actif? Type de cancer? TVP/EP symptomatique ou de découverte incidente? ESC 2014 Décision au cas par cas (évolution néoplasique; type de cancer, risque hémorragique,) Attitude devant de plus doit être réévalué régulièrement (ESC 2014)

Activité anti Xa