LE TRAITEMENT ANTITHROMBOTIQUE DE LA FA PROF L DE ROY UNIVERSITE DE LOUVAIN BELGIQUE

STROKE Rate in patients not taking warfarin, in AF 5.00 / year Rate in patients taking warfarin, in AF 1.35 / year Rate in patients not taking warfarin, in NSR 0.1 / year Relative risk for patients with previous stroke 2.0* * Risk of death from stroke Risk of permanent disability for survivors Rate in patients not taking warfarin, in AF 0.80 / year Rate in patients taking warfarin, in AF 1.46 / year Relative risk for patients with previous bleed 1.5* * Risk of death from major bleed Risk of morbidity for survivors of major bleed MAJOR BLEEDING EVENT * integer Greenberg 1998 Marcov Decision Analysis in AF AF : STROKE AND BLEEDING EVENTS

Stroke Prevention in Atrial Fibrillation: Warfarin Data Warfarin Better Warfarin Worse Combined SPINAF SPAF CAFA BAATAF AFASAK No. of Events Patient- Years Atrial Fibrillation Investigators. Arch Intern Med. 1994;154: RR: 69% (p<.001)

Stroke Prevention in Atrial Fibrillation: ASA Data Atrial Fibrillation Investigators. Arch Intern Med. 1994;154: Aspirin BetterAspirin Worse Risk Reduction, 19 % Combined SPAF AFASAK No. of Events Patient- Years

Antithrombotic therapy to prevent thromboembolism is recommended for ALL PATIENTS with AF, except those with lone AF or contraindications. Classe I IIa IIb III ABCABC PREVENTION DES THROMBO-EMBOLIES CONCEPT GENERAL Fuster V, Ryden LE, Cannom DS et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation Sep;8(9):

THROMBOEMBOLISM RISK FACTORS Major Risk Factors: - Valvular heart disease - Prosthetic heart valve - Prior CVA or TIA Moderate Risk Factors: - Age > 75 - HTN - Diabetes - CHF

Critères de risque CHADS 2 Score AVC ou AIT2 Age > 75 ans1 Hypertension1 Diabète1 Insuffisance cardiaque1 CHADS2 : évaluation du risque d’AVC chez des patients avec FA non valvulaire sans anticoagulation

Patients (N=1733) Risque ajusté d’AVC Ratio (% / an)* (IC 95%) Score CHADS ,9 (1,2 à 3,0)0 4632,8 (2,0 à 3,8)1 5234,0 (3,1 à 5,1)2 3375,9 (4,6 à 7,3)3 2208,5 (6,3 à 17,5)4 6512,5 (8,2 à 17,5)5 518,2 (10,5 à 27,4)6 * Le ratio ajusté d’AVC est dérivé d’une analyse multivariée ne comportant pas d’usage d’aspirine. Relation entre le score de CHADS2 et le risque d’AVC Arch Intern Med 2003;163:936–43 JAMA 2001;285:2864 –70

For primary prevention of thromboembolism in patients with nonvalvular AF who have just ONE of the MODERATE validated risk factors, antithrombotic therapy with either ASPIRIN OR A VITAMIN K antagonist is reasonable, Classe I IIa IIb III ABCABC PREVENTION DES THROMBO-EMBOLIES ASPIRINE OU AVK ?

Anticoagulation with a vitamin K antagonist is recommended for patients with >1 MODERATE RISK FACTOR Such factors include age over 75 years or greater, hypertension, heart failure, impaired left ventricular systolic function (ejection fraction 35% or less or fractional shortening less than 25%), and diabetes mellitus. Classe I IIa IIb III ABCABC PREVENTION DES THROMBO-EMBOLIES INDICATION DES ANTICOAGULANTS ORAUX

For patients with nonvalvular AF who have one or more of the following less well-validated risk factors, antithrombotic therapy with either ASPIRIN OR A VITAMIN K ANTAGONIST is reasonable for prevent i on of thromboembolism: age 65 to 74 years, female gender or coronary artery disease. The choice of agent should be based upon the risk of bleeding complications, ability to safely sustain adjusted chronic anticoagulation, and patient preferences. Classe I IIa IIb III ABCABC Fuster V, Ryden LE, Cannom DS et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation Sep;8(9): Prévention des thrombo-embolies FACTEURS DE RISQUE MOINS VALIDES

1.0 Odd ratio Accidents isch é miques H é morragies intracraniennes International Normalized Ratio RISQUE D’HÉMORRAGIE INTRACRANIENNE SELON L’INTENSITÉ DE L’ANTICOAGULATION

Long-term anticoagulation with a vitamin K antagonist IS NOT RECOMMENDED for primary prevention of stroke in patients ≤ 60 years without heart disease (lone AF) or risk factors for thromboembolism. Classe I IIa IIb III ABCABC PREVENTION DES THROMBO-EMBOLIES LONE AF + AVK ACC/AHA/ESC Guidelines Circulation 2006

In patients with AF < 60 years without heart disease or risk factors for thromboembolism (lone AF), the risk of thromboembolism is low without treatment and the effectiveness of aspirin for primary prevention of stroke relative to the risk of bleeding has not been established. Classe I IIa IIb III ABCABC PREVENTION DES THROMBO-EMBOLIES LONE AF + ASPIRINE

STENTS + FA

Clopidogrel should be given for a minimum of 1 month after implantation of a bare metal stent, at least 3 months for a sirolimus- eluting stent, at least 6 months for a paclitaxel-eluting stent and 12 months or longer in selected patients, following which warfarin may be continued as monotherapy in the absence of a subsequent coronary event. When warfarin is given in combination with clopidogrel or low-dose aspirin, the dose intensity must be carefully regulated. Classe I IIa IIb III ABCABC PREVENTION DES THROMBO-EMBOLIES STENTS

STENTS ANTIPLAQUETTAIRES ET AVK CONSENSUS 1.BMS: AAS: à vie CLOPIDOGREL 75 mg: 1 mois 2. DES: AAS + CLOPIDOGREL: 1 an AAS + CLOPIDOGREL: à vie (si haut risque) 3. INFARCTUS : AAS + CLOPIDOGREL: 1 an

STENTS ET ANTIAGREGANTS Guidelines for PCI EurHJ 2005

Rubboli Expert consensus document Ann Med 2008 HEMORRAGIES MAJEURES ET TRIPLE THERAPIE

QUID DES ANTIAGREGANTS?

ETUDE ACTIVE (BMS / Sanofi-Synthelabo) FA documentée Facteurs de risques cardio-vasculaires Eligible pour ACTIVE W : Clopidogrel (75 mg) + Aspirine (75 à 100 mg) versus Anticoagulant oral standard avec ajustement de la dose Eligible pour ACTIVE A : Clopidogrel (75 mg) + Aspirine (75 à 100 mg) versus Aspirine (75 à 100 mg) (double aveugle) ACTIVE I : Irbesartan versus Placebo (double aveugle) Follow-up : 3 ans (visites tous les 3 mois puis tous les 6 mois) Facteurs influençant le choix pour ACTIVE A

Connoly Lancet 2006 ACTIVE W

Hohnloser ACTIVE W JACC 2007

Healey ACTIVE: Risks and benefit Stroke 2008 ACTIVE + RISK FACTORS

Hohnloser ACTIVE W JACC 2007 n: 6706 pts

The Cochrane library 2008

Aspirin, mg daily, is recommended as an alternative to vitamin K antagonists in low-risk patients or in those with contraindications to oral anticoagulation. Classe I IIa IIb III ABCABC Fuster V, Ryden LE, Cannom DS et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation Sep;8(9): Prévention des thrombo-embolies ASPIRINE

For patients with AF who have mechanical heart valves, the target intensity of anticoagulation should be based on the type of prosthesis maintaining a INR of at least 2.5. Classe I IIa IIb III ABCABC Fuster V, Ryden LE, Cannom DS et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation Sep;8(9): Prévention des thrombo-embolies VALVES MECANIQUES

Antithrombotic therapy is recommended for patients with atrial flutter as for those with AF. Classe I IIa IIb III ABCABC Fuster V, Ryden LE, Cannom DS et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation Sep;8(9): Prévention des thrombo-embolies FLUTTER AURICULAIRE

In patients with AF who do not have mechanical prosthetic heart valves, it is reasonable to interrupt anticoagulation for up to one week without substituting heparin for surgical or diagnostic procedures that carry a risk of bleeding. Classe I IIa IIb III ABCABC Fuster V, Ryden LE, Cannom DS et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation Sep;8(9): Prévention des thrombo-embolies AVK ET INTERVENTION A RISQUE HEMORRAGIQUE

PATIENTS AGES?

n: 973 pts Mean age: 81.5 y BAFTA STUDY ELDERLY

In patients 75 years of age and older at increased risk of bleeding but without frank contraindications to oral anticoagulant therapy, and in other patients with moderate risk factors for thromboembolism who are unable to safely tolerate anticoagulation at the standard intensity of INR 2.0 to 3.0, a LOWER INR TARGET OF 2.0 (range 1.6 to 2.5) may be considered for primary prevention of ischemic stroke and systemic embolism. Classe I IIa IIb III ABCABC Fuster V, Ryden LE, Cannom DS et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation Sep;8(9): Prévention des thrombo-embolies AVK A DOSE MODEREE?

ET POUR LA CARDIOVERSION?

During the first 48 hours after onset of AF, the need for anticoagulation before and after cardioversion may be based on the patient’s risk of thromboembolism. Classe I IIa IIb III ABCABC Fuster V, Ryden LE, Cannom DS et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation Sep;8(9): Anticoagulation pour la cardioversion AVK ET FA < 48 h

As an alternative to anticoagulation prior to cardioversion of AF, it is reasonable to perform transesophageal echocardiography (TEE) in search of thrombus in the left atrium or left atrial appendage. Classe I IIa IIb III ABCABC Fuster V, Ryden LE, Cannom DS et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation Sep;8(9): Anticoagulation pour la cardioversion CARDIOVERSION RAPIDE

For patients with no identifiable thrombus, CARDIOVERSION is reasonable immediately after anticoagulation with UNFRACTIONATED HEPARIN (e.g., initiate by intravenous bolus injection and an infusion continued at a dose adjusted to prolong the activated partial thromboplastin time to 1.5 to 2 times the control value until oral anticoagulation has been established with a vitamin K antagonist (e.g., warfarin), as evidenced by an INR ≥ 2.0.). Classe I IIa IIb III ABCABC Fuster V, Ryden LE, Cannom DS et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation Sep;8(9): Anticoagulation pour la cardioversion CARDIOVERSION RAPIDE

Thereafter, oral anticoagulation (INR 2.0 to 3.0) is reasonable for a total anticoagulation period of at least 4 weeks, as for patients undergoing elective cardioversion. Classe I IIa IIb III ABCABC Fuster V, Ryden LE, Cannom DS et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation Sep;8(9): Anticoagulation pour la cardioversion CARDIOVERSION RAPIDE

Limited data are available to support the subcutaneous administration of a low-molecular-weight heparin in this indication. Classe I IIa IIb III ABCABC Fuster V, Ryden LE, Cannom DS et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation Sep;8(9): Anticoagulation pour la cardioversion CARDIOVERSION RAPIDE

ACUTE II TRIAL KLEIN 2006

For patients with atrial flutter undergoing cardioversion, anticoagulation can be beneficial according to the recommendations as for patients with AF. Classe I IIa IIb III ABCABC Fuster V, Ryden LE, Cannom DS et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation Sep;8(9): Anticoagulation pour la cardioversion FLUTTER AURICULAIRE

Targets for Antithrombotic treatment in atrial fibrillation Tissue factor Plasma Clotting Cascade Prothrombin Factor Xa Thrombin Fibrinogen Collagen ADP Thromboxane A 2 Conformational Activation of GPIIb/IIIa Platelet Aggregation Thrombus Fibrin ApixabanRivaroxaban Idraparinux AT DabigatranXimelagatran Aspirin ClopidogrelPrasugrelAZD6140Cangrelor

RE-LY TRIAL pts DABIGATRAN ETEXILATE vs WARFARINE (INR 2-3) ARISTOTLE TRIAL APIXABAN vs WARFARINE

CONCLUSIONS 1.Un traitement antithrombotique doit toujours être envisagé chez un patient en FAP, persistante ou permanente. 2.Une sélection judicieuse des patients et de l’antithrombotique s’impose néanmoins. 3.L’abstention est parfois recommandée. 4.Les nouveaux anticoagulants oraux sont attendus avec impatience