Tài liệu Atrial fibrillation role of new oral anticoagulants (For primary care doctors)

–Some risk factors are not recognized → underestimating stroke risk –Age is not a binary risk factor – rather, it is a continuum, with risk increasing with each decade from the age of 65 years onwards –CHADS2 classifies a substantial proportion of patients with AF as being at ‘moderate risk’ of stroke → their stroke risk may be underestimated → leading them to receive inadequate antithrombotic therapy for stroke prevention CHA2DS2-VASc: –More reliably identifies patients at low risk, with validation studies showing very few stroke events in patients categorized as being at low risk of stroke –Categorizes a small proportion of patients as intermediate risk –Simplifies selection of patients for anticoagulation, helping to remove much of the uncertainty regarding the optimal form of thromboprophylaxis Olesen JB et al. BMJ 2011;342:d124 Anticoagulation in AF Stroke Risk Reductions Hart R, et al. Ann Intern Med 1999;131:492 Warfarin Better Control Better AFASAK SPAF BAATAF CAFA SPINAF EAFT 100% 50% 0 -50% -100% Aggregate Reduction of stroke RRR = 64% Reduction of all cause mortality RRR = 26% Warfarin compared with Aspirin for stroke prevention in AF Hart RG et al. Ann Intern Med 2007;146:857–67 100 –100 50 0 –50 AFASAK I AFASAK II EAFT PATAF Warfarin better Aspirin better RRR 38% (95% CI: 18–52%) Chinese ATAFS SPAF II Age 75 yrs Age >75 yrs All trials Random effects model; Error bars = 95% CI; *P>0.2 for homogeneity; †Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic) STROKE RISK SCORE CHA2DS2-VASc Risk Score Patient CHF or LVEF < 40% 1 1 Hypertension 1 Age > 75 2 Diabetes 1 Stroke/TIA/ Thromboembolism 2 Vascular Disease 1 Age 65 - 74 1 1 Sex category (Female) 1 1 CHA2DS2-VASc = 3 - Lovenox 0,4 ml SC q12hrs - Sintrom 1 mg daily (with adjusment of dosage depending on the INR) - Digoxin ½ mg IV and Digoxin ¼ mg daily. - Zestril 5mg daily - Spiromide ( Furosemide 20mg/Spironolactone 50mg) daily MANAGEMENT INR 0 0.5 1 1.5 2 2.5 3 0 5 10 15 20 25 INR Days FOLLOWING INR 2 months later: - Presents to the CCU with sudden onset of right sided weakness. - Examination: . Oriented . Right side paralysis . HR: 90/m, irregular . BP: 120/70mmHg. - INR: 1,3 EVOLUTION Most strokes occurred in patients who were under-anticoagulated Association of stroke events with intensity of anticoagulation for patients with AF treated with warfarin in major randomized trials AFASAK SPINAF IN R 1.0 2.0 3.0 4.0 Target range for study ACC/AHA/ESC recommended INR (2.0–3.0) BAATAF CAFA SPAF INR at which stroke event occurred Levi M et al. Semin Thromb Haemost 2009;35:527–42 Routine coagulation monitoring Warfarin resistance Numerous drug–drug interactions Numerous food–drug interactions INR = International normalized ratio; VKA = vitamin K antagonist. Ansell J, et al. Chest 2008;133;160S-198S. Umer Ushman MH, et al. J Interv Card Electrophysiol 2008;22:129-137. Nutescu EA, et al. Cardiol Clin 2008;26:169-187. VKA therapy has several limitations that make it difficult to use in practice Frequent dose adjustments Unpredictable response Slow onset/ offset of action Narrow therapeutic window (INR: 2.0–3.0) Limitations of VKA therapy VKA for AF Limitations Lead to Inadequate Treatment Samsa GP, et al. Arch Intern Med 2000;160:967. INR above target 6% Subtherapeutic INR 13% INR in target range 15% No warfarin 65% Adequacy of Anticoagulation in Patients with AFib in Primary Care Practice Dose, Concentration, or Intensity of Anticoagulation T h ro m b o s is Safe Therapeutic Range Thrombosis Bleeding The Ideal Anticoagulant Wide Therapeutic Margin • At least as efficacious as current standard therapy • At least as safe as current standard therapy • Available for oral administration • Require no monitoring • No relevant interactions with food and common drugs • Cost-effective ... in order to aid treatment compliance and avoid the serious consequences of thrombosis and bleeding Requirements of new prophylactic agents NEW ORAL ANTICOAGULANTS ? Antithrombin Fibrinogen Factor II (Prothrombin) Fibrin Factor IIa (Thrombin) Factor X Factor IX Factor VII Anti-FXa drugs •Apixaban •Edoxaban •Rivaroxaban •Betrixaban Anti-FIIa drugs •Dabigatran •Ximelagatran Factor Xa VKA drugs •Warfarin •Sintrom FVIIa FIXa New oral anticoagulants Target sites Features Warfarin New Agents Onset Slow Rapid Dosing Variable Fixed Indications Same Same Food effect Yes No Drug interactions Yes Yes Monitoring Yes No Half-life Long Short Antidote Yes No Comparison of New oral anticoagulants with warfarin Rivaroxaban Apixaban Edoxaban Renal Clearance RE-LY Open Label Two Doses Twice Daily Renal Clearance ROCKET-AF Double Blind Two Doses Once Daily Hepatic Clearance ARISTOTLE Double Blind Two Doses Twice Daily Hepatic Clearance ENGAGE Double Blind Two Doses Once Daily Dabigatran Novel Anticoagulants FIIa Inhibitor Fxa Inhibitor New Oral Anticoagulants Important Comparative Features + Clinical trials Ruff CR and Giugliano RP. Hot Topics in Cardiology 2010;4:7-14 Ericksson BI, et al. Clin Pharmacokinet 2009;48:1-22 Dabigatran RE - LY Apixaban ARISTOTLE Rivaroxaban ROCKET - AF Edoxaban ENGAGE Target IIa (thrombin) Xa Xa Xa Time to peak levels 2 h 1-3 h 2-4 h 1-2 h Bioavailability 7% 66% 80% > 45% Half-life 12-14h 8-15h 9-13h 8-10h Renal elimination 80% 25% 33% 35% Dose 150 mg b.i.d 5 mg b.i.d 20 mg o.d 30mg/60mg qd Dose in renal impairment 110 mg b.i.d 2.5 mg b.i.d 15 mg o.d (if CrCl 30-49 ml/m) Special considerations Dabigatran: - Intestinal absorption is pH- dependent and is reduced in patients taking proton pump inhibitors - Increased risk of bleeding in patients takingverapamil/amiodarone/quinidine /ketoconazole Rivaroxaban: - Higher levels expected in patients with renal or hepatic failure - Activity lower in fasted patients so should be taken after food New Oral Anticoagulants Important Comparative Features + Clinical trials RE-LY R Warfarin (INR 2.0-3.0) N = 6022 Dabigatran Etexilate 110 mg bid N = 6015 Dabigatran Etexilate 150 mg bid N = 6076 PROBE=Prospective Randomized Open Trial with Blinded Adjudication of Events 10 efficacy outcome = stroke or systemic embolism 10 safety outcome = major bleeding Non-inferiority margin 1.46 open Blinded  Atrial fibrillation  ≥1 Risk Factor  Absence of contra-indications  951 centers in 44 countries 0.50 0.75 1.00 1.25 1.50 Dabigatran 110 vs Warfarin Dabigatran 150 vs Warfarin Non-inferiority P-value < 0.001 < 0.001 Superiority P-value 0.34 < 0.001 M a rg in = 1 .4 6 HR (95% CI) RE-LY Efficacy (Dabigatran) Stroke/Systemic Embolic Event Connolly, et al. N Engl J Med 2009;361:1139-51 0.1 0.3 0.5 1.0 2.0 Dabigatran 110 mg Dabigatran 150 mg Stroke/SEE Ischemic Stroke Hemorrhagic Stroke 0.91 (0.74-1.11) 0.66 (0.53-0.82) 1.11 (0.89-1.40) 0.76 (0.60-0.98) 0.31 (0.17-0.56) 0.26 (0.14-0.49) Dabigatran Better Warfarin Better RE-LY Efficacy (Dabigatran) 0.1 0.3 0.5 1.0 2.0 Major Bleed ICH GI Bleed 0.80 (0.69-0.93) 0.93 (0.81-1.07) 0.31 (0.20-0.47) 0.40 (0.27-0.60) 1.10 (0.86-1.41) 1.50 (1.19-1.89) MI 1.29 (0.96-1.75) 1.27 (0.94-1.71) Dabigatran Better Warfarin Better Dabigatran 110 mg Dabigatran 150 mg RE-LY Safety results (Dabigatran) Rivaroxaban Warfarin Primary End point: Stroke or non-CNS Systemic Embolism Statistics: non-inferiority, > 95% power, 2.3% warfarin event rate INR target - 2.5 (2.0-3.0 inclusive) 20 mg daily 15 mg for Cr Cl 30-49 Atrial Fibrillation Randomize Double blind / Double Dummy (n = 14,266) Risk Factors • CHF • Hypertension • Age  75 • Diabetes OR • Stroke, TIA or Systemic embolus At least 2 required Monthly Monitoring and adherence to standard of care guidelines 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 Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat through Site Notification populations 0.5 1 2 Patel, et al. N Engl J Med 2011;365(10);883-891 ROCKET AF Efficacy Stroke/Systemic Embolic Event ROCKET AF Key Secondary Efficacy Event Rivaroxaban (%/yr) Warfarin (%/yr) Hazard Ratio (95% CI) P- value Ischemic Stroke 1.34 1.42 0.94 (0.75-1.17) 0.581 Hemorrhagic Stroke 0.26 0.44 0.59 (0.37-0.93) 0.024 MI 0.91 1.12 0.81 (0.63-1.06) 0.121 Total Mortality 1.87 2.21 0.85 (0.70-1.02) 0.073 Vascular Mortality 1.53 1.71 0.89 (0.73-1.10) 0.289 Patel, et al. N Engl J Med 2011; 365(10);883-891 ROCKET AF Safety Event Rivaroxaban (%/yr) Warfarin (%/yr) Hazard Ratio (95% CI) P- value Major and Clinically Relevant Bleed 14.9 14.5 1.03 (0.96-1.11) 0.44 Major Bleed 3.6 3.4 1.04 (0.90-1.20) 0.58 Fatal Bleed 0.2 0.5 0.50 (0.31-0.79) 0.003 ICH 0.5 0.7 0.67 (0.47-0.93) 0.02 Patel, et al. N Engl J Med 2011; 365(10);883-891 Warfarin (target INR 2-3) Apixaban 5 mg oral twice daily (2.5 mg bid in selected patients) Primary outcome: stroke or systemic embolism Hierarchical testing: non-inferiority for primary outcome, superiority for primary outcome, major bleeding, death Randomize double blind, double dummy (n = 18,201) Inclusion risk factors Age ≥ 75 years Prior stroke, TIA, or SE HF or LVEF ≤ 40% Diabetes mellitus Hypertension Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device Exclusion  Mechanical prosthetic valve  Severe renal insufficiency  Need for aspirin plus thienopyridine ARISTOTLE Trial Design: Apixaban ARISTOTLE Efficacy: Apixaban Granger CB, et al. NEJM 2011; 365:981-992 HR 0.79 (0.66–0.95) P (non-inferiority) < 0.001 21% RRR (1.27 %/yr ) (1.60 %/yr) P (superiority) = 0.011 ARISTOTLE Efficacy Outcomes Granger CB, et al. NEJM 2011; 365:981-992 Outcome Apixaban (N = 9120) Warfarin (N = 9081) HR (95% CI) P Value Event Rate (%/yr) Event Rate (%/yr) Stroke or systemic embolism* 1.27 1.60 0.79 (0.66, 0.95) 0.011 Stroke 1.19 1.51 0.79 (0.65, 0.95) 0.012 Ischemic or uncertain 0.97 1.05 0.92 (0.74, 1.13) 0.42 Hemorrhagic 0.24 0.47 0.51 (0.35, 0.75) < 0.001 Systemic embolism (SE) 0.09 0.10 0.87 (0.44, 1.75) 0.70 All-cause death* 3.52 3.94 0.89 (0.80, 0.998) 0.047 Stroke, SE, or all-cause death 4.49 5.04 0.89 (0.81, 0.98) 0.019 Myocardial infarction 0.53 0.61 0.88 (0.66, 1.17) 0.37 ARISTOTLE Safety End Points Event Apixaban (%/yr) Warfarin (%/yr) Hazard Ratio (95% CI) P- value ISTH Major Bleeding 2.13 3.09 0.69 (0.60-0.80) < 0.001 ICH 0.33 0.80 0.42 (0.30-0.58) < 0.001 GUSTO Severe 0.52 1.13 0.46 (0.35-0.60) < 0.001 Gastrointestinal 0.76 0.86 0.89 (0.70-1.15) 0.37 Granger CB, et al. NEJM 2011; 365:981-992 ARISTOTLE: Apixaban Renal Function Hohnloser SH, et al. EHJ 2012 (epub August 29) Baseline Cockcroft-Gault eGFR mL/min A n n u a liz e d E v e n t R a te Stroke or SEE Major Bleeding Low dose regimen Edoxaban 30 mg qd (n ≈ 7000) Active Control Warfarin (n ≈ 7000) High dose regimen Edoxaban 60 mg qd (n ≈ 7000) AF on Electrical Recording < 12 mo Intended oral A/C CHADS2 >2 N = 21,105 R Randomization Stratified By 1. CHADS2 2-3 vs 4-6 2. Drug Clearance Median Duration of Follow-up 24 Months Primary Objective Edoxaban: Therapeutically as Good as Warfarin DOUBLE BLIND DOUBLE DUMMY 1º EP = Stroke or SEE (Noninferiority Boundary HR 1.38) 2º EP = Stroke or SEE or CV mortality Safety EP’s = Major Bleeding, Hepatic Function EVENT DRIVEN Ruff CR et al. Am Heart J 2010; 160:635-41 Phase III: Protocol Schema RE-LY (Dabigatran) ARISTOTLE (Apixaban) ENGAGE AF-TIMI 48* (Edoxaban) ROCKET-AF (Rivaroxaban) # Enrolled 18,113 18,201 21,105 14,264 Age (yrs) 72 ± 9 70 [63-76] 72 [64-77] 73 [65-78] Female 36% 35% 38% 40% CHADS2 score ≥3 32% 30% 52% 87% VKA naive 50% 43% 41% 38% Paroxysmal AF 33% 15% 25% 18% Prior stroke/TIA 20% 19% 18% / 12% 55%** Diabetes 23% 25% 36% 40% Prior CHF 32% 35% 56% 62% Hypertension 79% 87% 90% 91% * Preliminary data ** Includes prior systemic embolism Connolly SJ et al. N Engl J Med 2009; 361:1139-51 Patel MR et al. N Engl J Med 2011; 365:883-91 Granger CB et al. N Engl J Med 2011; 365:981-92 Ruff CR et al. Am Heart J 2010; 160:635-41 Pivotal Atrial Fibrillation Trials Baseline Characteristics Drug Dose (mg) RE-LY ROCKET-AF ARISTOTLE Dabigatran 110 bid 150 BID Rivaroxaban 20 mg qd Apixaban 5 mg bid Stroke + SEE non-infer Superior ITT cohort: non-infer. On Rx cohort: Superior Superior ICH Superior Superior Superior Superior Bleeding Lower similar similar Lower Mortality similar P = 0.051 similar Superior: P = 0.047 Ischemic stroke similar Lower similar similar Mean TTR 64% 55% 62% Stopped drug 21% 23% 23% WD consent 2.3% 8.7% 1.1% TTR = time in therapeutic range WD consent = withdrawal of consent, no further data available Pivotal Atrial Fibrillation Trials Results to Date Efficacy of New Oral Anticoagulants Favors NOACs Favors Warfarin 13% 55% Hemorraghic Stroke Ischemic & Unsp. Stroke Stroke & SEE The American Journal of Cardiology Volume 110, Issue 3 2012 453 - 460 Safety of New Oral Anticoagulants GI Major bleeding Gastrointestinal bleeding Incranial bleeding The American Journal of Cardiology Volume 110, Issue 3 2012 453 - 460 51% Favors NOACs Favors Warfarin Despite continued use of warfarin, NOACs are considered by many professional medical organizations to be the “best option” for anticoagulation of SPAF patients: – ESC 2012 AF Update Guidelines – ACCP 2012 Guidelines – Canadian AF Guidelines “Best Options” for Anticoagulation The Consensus is Shifting Atrial fibrillation < 65 years and lone AF (including females) Assess risk of stroke CHA2DS2-VASc Assess bleeding risk (HAS-BLED score) Consider patient values and preferences No antithrombotic therapy Oral anticoagulant therapy NOAC VKA 0 1 No ( i.e non-valvular AF) Yes No ≥2 Valvular AF * C