Engage af timi 48 - lawrie


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Edoxaban vs warfarin in non-valvular AF

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Engage af timi 48 - lawrie

  1. 1. Edoxaban vs Warfarin in Patients with Atrial Fibrillation ENGAGE AF-TIMI 48 Trial Faraz Lawrie Department of Cardiology Changi General Hospital
  2. 2. BACKGROUND • Atrial fibrillation is the most common arrhythmia affecting 0.4 to 1% of the general population • In individuals over the age of 80 the prevalence increases to 8% • The risk of stroke is increased 5-fold in individuals with atrial fibrillation • Strokes from AF account for 6-24% of all ischemic strokes • The mainstay for stroke prevention in AF has historically been VKAs.
  3. 3. BACKGROUND Assessment of Stroke Risk using CHA2DS2-VASc
  4. 4. BACKGROUND • OAC indicated for score >=2 • OAC (preferred) vs Aspirin for score 1(unless due to female gender alone) • No anticoagulation for score 0 • OAC use associated with significant risk of bleeding • Bleeding risk prognostication: HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile International Normalized Ratio, Elderly, Drugs/alcohol concomitantly) • Score of ≥3 indicates "high risk“ • Warfarin is the standard OAC
  5. 5. WARFARIN: a double-edged sword Why we hate it! Maybe not so bad! Narrow therapeutic window 50+ years experience Sensitive to changes in diet Simple standardized test for functional level (INR) Slow to act, very long half-life Reversal agents highly effective and readily available Numerous drug interactions No side effects except bleeding Wide range in therapeutic doses Generic and cheap • By some estimates, only 40-60% patients meeting guideline criteria are treated with warfarin. • Approximately 60-65% are within therapeutic range
  6. 6. NOACs: A New Hope Dabigatran Apixaban Edoxaban RIvaroxaban Action Direct Thrombin Inhibitor Activated Factor Xa Inhibitor Activated Factor Xa Inhibitor Activated Factor Xa Inhibitor Dose 150 mg bid 110 mg bid 5 mg bid 2.5 mg bid 60 mg qd 30 mg qd 15 mg qd 20 mg qd 15 mg qd Phase 3 Clinical Trial RE-LY ARISTOTLE AVERROES ENGAGE AF ROCKET AF
  7. 7. EDOXABAN • oral, reversible, direct factor Xa inhibitor with a linear and predictable pharmacokinetic profile and 62% oral bioavailability • achieves maximum concentrations within 1 to 2 hours • 50%/50% excretion by kidney/liver • The Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial is a three-group, randomized, double-blind, double-dummy trial comparing two dose regimens of edoxaban with warfarin conducted at 1393 centres in 46 countries with enrolment through November 19, 2008 to November 22, 2010
  8. 8. Study Population • • • • • • • • • • • • • Inclusion Criteria Age>21 years Documented AF on ECG within 12 months preceding randomization Score >=2 on CHADS2 Anticoagulation therapy planned for the duration of the trial Exclusion criteria Atrial fibrillation due to a reversible disorder Estimated creatinine clearance < 30 ml/min high risk of bleeding use of dual antiplatelet therapy moderate-to-severe mitral stenosis other indications for anti -coagulation therapy acute coronary syndromes, coronary revascularization, or stroke within 30 days before randomization • inability to adhere to study procedures
  9. 9. Study Design • Patients were randomly assigned, in a 1:1:1 ratio, to receive warfarin, dose-adjusted to achieve an INR of 2.0 to 3.0, or to receive high-dose or low-dose edoxaban • Patients already on VKA were randomized after INR<2.5 • High dose Edoxaban group: default 60 mg qd • Low dose Edoxaban group: default 30 mg qd • For either group, dose halved if at randomization or during period of study:• estimated creatinine clearance of 30 - 50 ml/min • Weight<60 kg • Concomitant P-glycoprotein inhibitors: Verapamil, Quinidine, Dronedarone
  10. 10. Study Design • Double dummy: each patient received two sets of study drugs: either active edoxaban and a placebo matching warfarin, or a placebo matching edoxaban and active warfarin. • sham INR values were generated for patients who were randomly assigned to edoxaban • At the end of the trial, patients made the transition to openlabel oral anticoagulation therapy • Primary efficacy end point: time to the first adjudicated stroke (ischemic or haemorrhagic) or systemic embolic event • Principal safety end point: adjudicated major bleeding
  11. 11. RESULTS: The Big Picture • A total of 21,105 patients underwent randomization, of whom 21,026 (99.6%) received the study drug • Complete information on the primary end point was ascertained for 99.5% of the total 56,346 patient-years of potential follow-up • median duration of treatment exposure was 907 days • median follow-up was 1022 days • For warfarin group the median time in the therapeutic range was 68.4% of the treatment period with the INR being between 1.8 and 3.2 for 83.1% of this period
  12. 12. RESULTS: The Big Picture • A stroke or systemic embolic event occurred in 232 patients in the warfarin group (representing a rate of 1.50% per year), as compared with 182 patients in the high-dose edoxaban group (a rate of 1.18% per year; hazard ratio vs. warfarin, 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; P<0.001 for noninferiority, P = 0.02 for superiority) and 253 patients in the low-dose edoxaban group (a rate of 1.61% per year; hazard ratio vs. warfarin, 1.07; 97.5% CI, 0.87 to 1.31; P = 0.005 for non-inferiority, P = 0.44 for superiority) • The rate of major bleeding events was 3.43% per year with warfarin, as compared with 2.75% per year with high-dose edoxaban (hazard ratio, 0.80; 95% CI, 0.71 to 0.91; P<0.001) and 1.61% per year with low-dose edoxaban (hazard ratio, 0.47; 95% CI, 0.41 to 0.55; P<0.001)
  13. 13. RESULTS: The Big Picture • The rate of stroke or systemic embolic event was lower with high-dose edoxaban than with low-dose edoxaban (P<0.001); there was a relative reduction in the incidence of ischemic stroke of 29% with high-dose edoxaban, which more than offset a higher incidence of haemorrhagic stroke(which however had more significant sequelae) • As compared with high-dose edoxaban, low-dose edoxaban was associated with significantly lower rates of bleeding, including major bleeding, intracranial bleeding, and major or clinically relevant non-major bleeding
  14. 14. Kaplan Meier Curve for Primary Efficacy End Point
  15. 15. Kaplan Meier Curve for Primary Safety End Point
  16. 16. Discussion • Both edoxaban regimens are non -inferior to well-managed warfarin (median time in the therapeutic range, 68.4% of the treatment period) for the prevention of stroke or systemic embolic event with the high-dose edoxaban regimen being more effective than warfarin • The incidence of haemorrhagic stroke, all types of bleeding and major cardiovascular events are significantly lower with both edoxaban regimens than with warfarin with the exception being GI bleeding, which occurred more frequently with high-dose edoxaban but less frequently with low-dose edoxaban than it did with warfarin
  17. 17. Discussion • Intergroup variations between groups stratified by age, geography, prior/concomitant drug usage and risk of stroke were not significant except:• VKA naïve patients had significantly fewer stroke or systemic embolic events with high-dose edoxaban than with warfarin, whereas the rates were similar among non-naïve patients • Concomitant amiodarone or aspirin augmented the action of lowdose edoxaban • Dose reduction of edoxaban in age<60, impaired creatinine clearance and concomitant P-glycoprotein inhibitors groups reduced bleeding risk
  18. 18. Discussion • Strengths of the ENGAGE AF-TIMI 48 trial • • • • large sample size long follow-up minimal amount of missing data greater-than-average time in the therapeutic range in the warfarin group • inclusion of multiple once-daily doses of a new anticoagulant agent ranging from 15 to 60 mg with dynamic dose modification • Comprehensive transition plan to open-label anticoagulation therapy resulted in a low and evenly distributed number of events after the discontinuation of study therapy making it unlikely that there is a rebound activation of coagulation after the discontinuation of edoxaban • In conclusion, both once-daily regimens of edoxaban were noninferior to warfarin for the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes.
  19. 19. The View from 30k feet RE-LY ROCKET AF ARISTOTLE ENAGAGE AF Study Design Warfarin open label; Dabigatran blinded Double-blind, double dummy Double-blind, double dummy Double-blind, double dummy Comparison Dabigatran 110/150 mg bid vs warfarin Rivaroxaban 20 mg qd vs warfarin Apixaban 5 mg bid vs warfarin Edoxaban 15/30/60 mg qd vs warfarin Primary End Point Stroke or systemic embolism Stroke or systemic embolism Stroke or systemic embolism Stroke or systemic embolism Size 18113 14264 18201 21026 Followup 2 1.9 1.8 2.3
  20. 20. The View from 30k feet: Caveat Emptor RE-LY 110/150 ROCKET AF ARISTOTLE ENAGAGE AF Hi/lo Mean TTR Warfarin 64 55 62 68 Stroke or Systemic Embolism 0.90/0.65 0.88 0.79 0.79/1.07 Haemorrhagic 0.31/0.26 Stroke 0.59 0.51 0.54/0.33 Major Bleeding 0.80/0.93 1.04 0.69 0.80/0.47 ICH 0.30/0.41 0.67 0.42 0.47/0.30 MI 1.29/1.27 0.81 0.88 0.94/1.19 GI Bleed 1.08/1.48 NA 0.89 1.23/0.67 All Cause mortality 0.91/0.88 0.92 0.89 0.92/0.87
  21. 21. Thank You • There are no silver bullets in medicine • We are always free to choose our own poison