Πρόοδος στην αντιπηκτική αγωγή

Πρόοδος στην αντιπηκτική αγωγή Βασίλειος Π. Βασιλικός MD, FACC, FESC Αναπληρωτής Καθηγητής ΑΠΘ

AF increases the risk of stroke AF is associated with a pro-thrombotic state ~5 fold increase in stroke risk Risk of stroke is the same in AF patients regardless of whether they have paroxysmal or sustained AF AF-related stroke has a 1-year mortality of ~50%

AF-related stroke is preventable 2/3 of strokes due to AF are preventable with appropriate anticoagulant therapy with a vitamin-k-antagonist (INR 2-3) 1 Anticoagulation with a vitamin-kantagonist (VKA) is recommended for patients with more than 1 moderate risk factor 2 Effect of VKA compared to placebo Stroke Death A meta-analysis of 29 trials in 28,044 patients showed that adjusted-dose warfarin results in a reduction in ischaemic stroke and in all-cause mortality 1 67% 26% 1. Hart RG et al. Ann Intern Med. 2007;146:857-867 2. Fuster V, et al. JACC. 2006; 48: 854-906

Limitations of VKA therapy

% of eligible patients receiving warfarin INR control: clinical trials vs clinical practice INR* control in clinical trial versus clinical practice (TTR**) 66% Clinical trial 1 Clinical practice 2,3 38% 44% 25% 18% 9% <2.0 2.0 3.0 >3.0 INR *INR = International normalized ratio ** TTR = Time in Therapeutic Range (INR2.0-3.0) 1. Kalra L, et al. BMJ 2000;320:1236-1239 * Pooled data: up to 83% to 71% in individualized trials; 2. Samsa GP, et al. Arch Int Med 2000 3. Matchar DB, et al. Am J Med 2002; 113:42-51.

Management of AF in clinical practice: prescription of vitamin K antagonists No anticoagulation Vitamin K antagonists n = 23,657 Medicare cohort, U.S.A. Birman-Deych E, et al. Stroke 2006; 37: 1070 n = 5,333 EuroHeart survey Nieuwlaat R, et al. Eur Heart J 2005; 26:2422 n = 11,379 ATRIA cohort (managed care system, California, U.S.A.) Go AS, et al. JAMA 2003; 290: 2685

Αμηιπηκηική θεοαπεία ζε αζθεμείπ ηλικίαπ μεγαλύηεοηπ ηωμ 75 εηώμ με παοξνρζμική κξλπική μαομαοργή(%) 100 90 80 70 60 50 40 30 20 10 0 p<0,01* 57 45 30 19 15 21 6 5 OXΙ ΣΠΑΝΙΑ ΣΥΦΝΑ ΠΑΝΤΟΤΕ ΚΑΡΔΙΟΛΟΓΟΙ ΜΗ ΚΑΡΔΙΟΛΟΓΟΙ Vassilikos et al, HJC 2010

Αμηιπηκηική αγωγή ζε ρπεοηαζικξύπ ή διαβηηικξύπ αζθεμείπ με μόμιμη κξλπική μαομαοργή ςωοίπ ξογαμική καοδιακή μόζξ 100 90 94 84 p<0,01* 80 70 60 50 40 ΚΑΡΔΙΟΛΟΓΟΙ ΜΗ ΚΑΡΔΙΟΛΟΓΟΙ 30 20 10 6 16 0 ΝΑΙ OΦΙ Vassilikos et al, HJC 2010

CHADS2 vs CHA2DS2-VASC Gage at al, JAMA 2001 Lip et al, Chest 2010

Novel anticoagulants

Σφνοψη των κυριότερων αποτελεςμάτων των 3 μεγάλων κλινικϊν δοκιμϊν των νεϊτερων αντιπηκτικϊν RELY (150mg) (n=3x6000) ROCKET-AF (n=2x7000) ARISTOTLE (n=2x9000) Design Open label (PROBE design) Double blind high risk pts Double blind lower risk pts CHADS score 2.1 3.5 2.1 TTR achieved 67% (64% mean) 56% 66% Stroke and non- CNS Embolism Hemorrhagic stroke 0.65 (P<0.001) 0.79 (0.015) PP 0.88 (0.12) ITT 0.79 (P=0.01) 0.26 (P<0.001) 0.59 (0.024) 0.51 (P<0.001) Total mortality 0.88 (P=0.051) 0.85 (P=0.073) 0.89 (P=0.047) Intracranial bleeding Major/critical bleeding 0.32 (P<0.001) 0.67 (P=0.003) 0.42 (P<0.001) 0.80 (P=0.03) 0.69 (P=0.007) 0.68 (P=0.01)

all-cause stroke and systemic embolism ischemic and unspecified stroke hemorrhagic stroke Miller et al, AJC 2012

major bleeding intracranial bleeding gastrointestinal bleeding Miller et al, AJC 2012

Approach to thromboprophylaxis in patients with AF Camm et al. Eur Heart J 2010

Japanese scientific statement on dabigatran Non-valvular AF 2 points CHADS 2 score 1 points Other risk factors 65 74 yrs Female CAD or cardiomyopathy Thyrotoxicosis Recommended Dabigatran Warfarin* Recommended Dabigatran Option to be considered Warfarin* Options to be considered Dabigatran Warfarin* 22 Available at: http://www.j-circ.or.jp/guideline/pdf/statement.pdf

2012 ACCP guidelines for antithrombotic therapy in patients with AF (I) Patient features Low risk of stroke (e.g. CHADS 2 = 0) Intermediate risk of stroke (e.g. CHADS 2 = 1) High risk of stroke (e.g. CHADS 2 = 2) Recommended antithrombotic therapy None (rather than antithrombotic therapy) Oral anticoagulation (rather than no therapy, Aspirin, or Aspirin + clopidogrel)) Dabigatran 150 mg BID (rather than dose-adjusted VKA*) Oral anticoagulation (rather than no therapy, Aspirin, or Aspirin + clopidogrel) Dabigatran 150 mg BID (rather than dose-adjusted VKA*) Previous stroke/tia Oral anticoagulation (rather than no therapy, Aspirin, or Aspirin + clopidogrel) Dabigatran 150 mg BID (rather than dose-adjusted VKA*) BID = twice daily; TIA = transient ischaemic attack; VKA = vitamin K antagonist *Target range for international normalized ratio: 2.0 3.0 You JY et al. Chest 2012;141;e531S e575s

HAS-BLED new bleeding risk scoring system Hypertension Abnormal renal/liver function Stroke Bleeding history or predisposition Labile INR Elderly (>65) Drugs/alcohol concomitantly R. Pisters and GYHL. Lip et al. Chest: prepublished online March 18, 2010

Clinical considerations Increased risk for bleeding Age Renal function Prescription patterns

64000 pts since Jan 2011 81 serious side effects 5 deaths due to fatal bleeding One had renal failure, 4 were >80year old

EMA safety report (dabigatran) Data up to November 2011 256 serious bleedings resulting in death (EudraVigilance database) 21 reported in EU

USA Up to Oct 2011 in the US 410 000 patient-treatment-years, which translates into a rate of 63 events per 100 000 patienttreatment-years 0.23% per year: 230 per 100 000 patient-years (150mg bd RELY) 0.33% per year: 330 per 100 000 patient-years (warfarin RELY)

Committee for Medicinal Products for Human Use (CHMP): New recommendations Renal function be assessed in all patients before starting treatment While on treatment, renal function should be assessed at least once a year in patients over 75 years of age and whenever a decline in renal function is suspected in patients of any age

Kansal et al Heart 2012

Kansal et al Heart 2012

Freeman et al, Ann Int Med 2011

Συμπεράςματα Η αντιθρομβωτικό αγωγό προτιμότερη ςτουσ «μϋςου» κινδύνου αςθενεύσ με ΚΜ Τα νϋα αντιθρομβωτικϊ φϊρμακα εύναι αποτελεςματικϊ ςτην πρόληψη ΑΕΕ Μικρότερεσ πιθανότητεσ αιμορραγιών ςε ςχϋςη με βαρφαρύνη Παρακολούθηςη και καταγραφό τησ κλινικόσ ςυμπεριφορϊσ τουσ ςε «πραγματικϋσ» ςυνθόκεσ

Kansal et al Heart 2012

Eikelboom et al, Circulation 2011

Eikelboom et al, Circulation 2011

2012 ACCP guidelines for antithrombotic therapy in patients with AF (II) Patient features Atrial flutter Recommended antithrombotic therapy Same risk-based recommendations as for AF Mitral stenosis Oral anticoagulation (rather than no therapy, Aspirin, or Aspirin + clopidogrel) Dose-adjusted VKA* Stable CAD Oral anticoagulation (rather than dose-adjusted VKA + Aspirin) Dose-adjusted VKA* Intracoronary stent If high risk of stroke (CHADS 2 2): Triple therapy (VKA, Aspirin, clopidogrel) during month after bare-metal stent OR 3 6 months after drug-eluting stent (rather than dual AP therapy) Dose-adjusted VKA* + single AP therapy after initial period of triple therapy (rather than VKA alone) Antithrombotic therapy as for stable CAD, after 12 months If low/intermediate risk of stroke (CHADS 2 1): Dual AP therapy for 12 months after stent placement (rather than triple therapy) Antithrombotic therapy as for stable CAD,after 12 months