new oral anticoagulants versus warfarin-appraisal

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new oral anticoagulants versus warfarin-appraisal

  1. 1. Presented by: Dr.Venugopalan.G, JR Preceptor: Dr. Pradeep Behl, SR Department of Geriatric Medicine
  2. 2.
  3. 3.  Meta-analysis is a systematic review of a focused topic in the literature that provides a quantitative estimate for the effect of a treatment intervention or exposure Meta-analysis Mark W. Russo How to Review a Meta-analysis.Gastroenterology & Hepatology Volume 3, Issue 8 August 2007
  4. 4.  AF is defined as a cardiac arrhythmia with the following characteristics:  The surface ECG shows ‘absolutely’ irregular RR intervals  There are no distinct P waves on the surface ECG  The atrial cycle length is usually variable and <200 ms (>300 bpm). Atrial Fibrillation-definition
  5. 5.  Previous stroke or TIA  Age > 75  Structural heart disease  Hypertension  Previous MI  Moderate to severe LV dysfunction in echo  Complex aortic plaque in TOE  Marked LA enlargement(>5.0 cm) Risk factors for stroke in AF Diabetes-Not a convincing predictive factor Michael Hughes et al. Stroke and thromboembolism in atrial fibrillation: A systematic review. Thromb Haemost 2008; 99: 295–304
  6. 6.  CHADS2 score C Congestive Heart Failure 1 point H Hypertension 1 point A Age75 y 1 point D Diabetes 1 point S2 Stroke 2 points Score 0=aspirin Score 1=aspirin or oral anticoagulation Score 2=oral anticoagulation
  7. 7.  CHADS2 & Stroke rate Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864–2870
  8. 8.  CHA2DS2-VASc Score C Congestive Heart Failure 1 point H Hypertension 1 point A2 Age_75 y 2 points D Diabetes 1 point S2 Stroke 2 points V Vascular disease 1 point A Age_65 y 1 point Sc Sex category, female 1 point Score 0= no therapy or aspirin (no therapy preferred) Score 1= aspirin or oral anticoagulation (oral anticoagulation preferred) Score 2= oral anticoagulation
  9. 9.  Mason et al CHA2DS2-VASc Score and Anticoagulation for Atrial Fibrillation. The American Journal of Medicine, Vol 125, No 6, June 2012
  10. 10.  HAS-BLED H Hypertension 1 A Abnormal renal and liver function(1 point each) 1 or 2 S Stroke 1 B Bleeding 1 L Labile INRs 1 E Elderly (>65 years) 1 D Drugs or alcohol (1 point each) 1 or 2 Score > 3 is high risk for bleeding
  11. 11.  ESC guidelines 2010
  12. 12.  ESC guidelines 2010
  13. 13.   For patients with AF, (including paroxysmal AF) who are at low risk of stroke (eg, CHADS2 score=0), we suggest no therapy rather than antithrombotic therapy (Grade 2B)  For patients who do choose antithrombotic therapy, we suggest aspirin (75 mg to 325 mg once daily) rather than oral anticoagulation (Grade 2B) or combination therapy with aspirin and clopidogrel (Grade 2B) Antithrombotic Therapy for Atrial Fibrillation ACCP guidelines 9th ed. CHEST 2012; 141(2)(Suppl):e531S–e575S
  14. 14.   Who are at intermediate risk of stroke (eg, CHADS2 score=1), we recommend oral anticoagulation rather than no therapy (Grade 1B) . We suggest oral anticoagulation rather than aspirin or combination therapy(Grade 2B).  For patients who are unsuitable for or choose not to take an oral anticoagulant, we suggest combination therapy with aspirin and clopidogrel rather than aspirin(Grade 2B) Antithrombotic Therapy for Atrial Fibrillation ACCP guidelines 9th ed. CHEST 2012; 141(2)(Suppl):e531S–e575S
  15. 15.   Who are at high risk of stroke (eg, CHADS2 score= 2), we recommend oral anticoagulation rather than no therapy (Grade 1A) , aspirin or combination therapy(Grade 1B).  For patients who are unsuitable for or choose not to take an oral anticoagulant, we recommend combination therapy with aspirin and clopidogrel rather than aspirin(Grade 1B) Antithrombotic Therapy for Atrial Fibrillation ACCP guidelines 9th ed. CHEST 2012; 141(2)(Suppl):e531S–e575S
  16. 16.   For patients with AF, (including paroxysmal AF) for recommendations in favor of oral anticoagulation we suggest dabigatran 150 mg bd rather than adjusted-dose warfarin (target INR range, 2.0-3.0) (Grade 2B)  Exception: AF with MS, AF with CAD Antithrombotic Therapy for Atrial Fibrillation ACCP guidelines 9th ed. CHEST 2012; 141(2)(Suppl):e531S–e575S
  17. 17.   AF and Mitral Stenosis: warfarin (INR-2.0 to 3.0)  AF with stable CAD: warfarin (INR-2.0 to 3.0)  AF with high risk and 1st month of bare metal stent or 3 to 6 month of drug eluting stent: triple therapy (warfarin, aspirin, clopidogrel).  After this period till 12 motnhs: warfarin and aspirin/clopidogrel  After 12 months: same as AF with stable CAD Antithrombotic Therapy for Atrial Fibrillation ACCP guidelines 9th ed. CHEST 2012; 141(2)(Suppl):e531S–e575S
  18. 18.   AF with low/intermediate risk till 12 months of stent: dual antiplatelet therapy  After this period: same as AF with stable CAD  AF with acute CAD, no stent, till 12 months: warfarin plus aspirin/clopidogrel  After this period: same as AF with stable CAD Antithrombotic Therapy for Atrial Fibrillation ACCP guidelines 9th ed. CHEST 2012; 141(2)(Suppl):e531S–e575S
  19. 19.   In pts “unsuitable” for oral anticoagulation due to a specific risk of bleeding, patient preference or physician preference  Reduced the risk of major vascular events (6.8% vs 7.6% per year), especially stroke(2.4% vs 3.3% per year)  Increased the risk of major hemorrhage (2.0% vs 1.3% per year) ACTIVE-A (Effect of Clopidogrel Added to Aspirin in Patients with Atrial Fibrillation) trial Class IIb in 2011 ACCF/AHA/HRS Focused Update on the Management of Patients With AFib
  20. 20.  Oral Anticoagulants
  21. 21.  Warfarin  Vitamin K antagonist  Oral, i.v, rectal-bioavailability nearly complete  T1/2=25 to 60 hours (≈40 hours), duration of action= 2 to 5 days  Monitoring: PT(INR)  Antidote: Vitamin K1(phytonadione), FFP Vitamin K antagonist
  22. 22.   Genotype testing for CYP2C9 and VKORC1 (FDA suggested)  Slow onset and offset of action (TTI)  Narrow therapeutic range  Regular monitoring (TTR)  Drug interactions Problems with warfarin TTI- Time To INR TTR- Time in Therapeutic Range
  23. 23.   Direct Thrombin inhibitors:  Ximelagatron  Dabigatran  Factor Xa inhibitors:  Rivaroxaban  Apixaban  Edoxaban New OAC
  24. 24.  Direct Thrombin inhibitor (both free and clot bound IIa)  T1/2=12 – 17 hours  GFR >30ml/min:150 mg bd, GFR 15 to 30 ml/min: 75 mg bd  90-95% unchanged in urine, rest in bile. Dialysable.  PT, aPTT, TT  No antidote. Prothrombin concentrate or rVIIa may be used.  RE-ALIGN trial: significantly more thromboembolic events and excess of major bleeding in patients with prosthetic heart valves Dabigatran
  25. 25.  Randomized Evaluation of Long Term Anticoagulation Therapy N Engl J Med 2009; 361:1139-51(RE-LY; dabigatran) Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism, According to Treatment Group
  26. 26.  As compared to warfarin(1.69% per year of 1⁰ outcome):  Dabigatran 110 mg- similar rate(1.53% per year) of stroke and systemic embolism, lower rates of major haemorrhage.  Dabigatran 150 mg-lower rates(1.11% per year) of stroke and systemic embolism, similar rates of major haemorrhage Randomized Evaluation of Long Term Anticoagulation Therapy N Engl J Med 2009; 361:1139-51(RE-LY; dabigatran)
  27. 27.  Reversible Factor-Xa inhibitor, activity also on thrombin and factor VII  T1/2=5-13 hours  20 mg od, if GFR 30 to 49 ml/min: 15 mg od  CYP3A4 metabolism, 70% renal and 30%fecal elimination  No antidote. Prothrombin concentrate or rVIIa may be used.  Monitoring: anti Factor Xa assay, PT, aPTT  It is not for patients with artificial heart valves Rivaroxaban
  28. 28.  Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) N Engl J Med 2011;365:883-91
  29. 29.   1.7% per year vs 2.2% per year (P<0.001 for non-inferiority)  2.1% per year vs 2.4% per year (P = 0.12 for superiority)  There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group  Funded by Johnson & Johnson and Bayer Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) N Engl J Med 2011;365:883-91
  30. 30.   Reversible Factor-Xa inhibitor  T1/2=8-15 hours  5 mg bd  CYP3A4 metabolism. 30% renal and 70% fecal elimination  Minimal p-gp interaction  Anti factor Xa assay, PT, aPTT  No antidote Apixaban
  31. 31.  Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) N Engl J Med 2011;365:981-92.
  32. 32.   Apixaban reduced the risk of (in comparison to warfarin)  stroke or systemic embolism by 21%  major bleeding by 31% and  death by 11%.  Apixaban (5mg bd/ 2.5 mg bd in subsets) was superior to warfarin  Funded by Bristol-Myers Squibb and Pfizer Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) N Engl J Med 2011;365:981-92.
  33. 33.   Reversible Factor Xa inhibitor  T1/2=9-10 hours  50% renal clearance  60 mg od  Anti factor Xa assay, PT, aPTT  No antidote Edoxaban
  34. 34.  Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF–TIMI 48) N Engl J Med 2013;369:2093-104
  35. 35.  Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF–TIMI 48) N Engl J Med 2013;369:2093-104
  36. 36.   Both (30mg & 60mg) once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes  Funded by Daiichi Sankyo Pharma Development Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF–TIMI 48) N Engl J Med 2013;369:2093-104
  37. 37.  Novel Oral Anticoagulants in Atrial Fibrillation: A Meta-analysis of Large, Randomized, Controlled Trials vs Warfarin Ariel Dogliotti, Ernesto Paolasso, Robert P. Giugliano. Clin. Cardiol. 36, 2, 61–67 (2013)
  38. 38.
  39. 39.   To assess the relative benefit of new oral anticoagulants in key subgroups  And to assess the effects on important secondary outcomes. Aim
  40. 40.   Search: Medline from Jan 1, 2009, to Nov 19, 2013  Limited to phase 3, RCTs of patients with atrial fibrillation who were randomised to receive new oral anticoagulants or warfarin, and  Trials in which both efficacy and safety outcomes were reported for their comparison Study selection
  41. 41.   Pre specified analysis of the four phase 3 randomised trials ROCKET AF ARISTOTLE  RE LY ENGAGE AF TIMI 48 Study selection
  42. 42.   Stroke and systemic embolic events,  Ischaemic stroke,  Haemorrhagic stroke,  All-cause mortality,  Myocardial infarction,  Major bleeding,  Intracranial haemorrhage (including haemorrhagic stroke, epidural, subdural and subarachnoid haemorrhage), and  Gastrointestinal bleeding Outcomes Efficacy Safety
  43. 43.  Median follow-up: 1.8 to 2.8 years Participants 71,683 42,411 29,272 Novel oral anticoagulants Warfarin
  44. 44.
  45. 45.  1) Meta analysis done for both higher doses (dabigatran 150 mg bd and edoxaban 60 mg od) combined with the single doses studied in ROCKET AF(rivaroxaban 20 mg od) and ARISTOTLE(apixaban 5 mg bd) 2) In a separate analysis a meta-analysis of the two lower doses (dabigatran 110 mg bd and edoxaban 30 mg od) Statistical Analysis
  46. 46.  Statistical Analysis Two sensitivity analyses were also done: 1) A meta-analysis of only the factor Xa inhibitors, with removal of the thrombin inhibitor dabigatran 2) An analysis combining all doses of all drugs (both high and low doses of dabigatran and edoxaban with rivaroxaban and apixaban)
  47. 47.  Stroke or systemic embolic events
  48. 48.  Secondary efficacy and safety outcomes
  49. 49.  Major bleeding
  50. 50.   Age (<75 vs ≥75 years)  Sex  H/O previous stroke or TIA,  H/O diabetes,  Renal function (creatinine clearance <50 ml/min, 50– 80 ml/min, >80 ml/min),  CHADS2 risk score (0–1, 2, 3–6),  VKA status at study entry (naive or experienced), and  Centre-based time in therapeutic range (threshold of <66% vs ≥66%) Subgroup analysis Compared efficacy and safety in important clinical subgroups
  51. 51.  Stroke or systemic embolic events in subgroup
  52. 52.  Major bleeding in subgroup
  53. 53.   Stroke and systemic embolic events were significantly reduced in patients receiving new oral anticoagulants.  This benefit was mainly driven by substantial protection against haemorrhagic stroke, which was reduced by half  Significant reduction in all cause-mortality compared with warfarin Discussion
  54. 54.   For the prevention of ischaemic stroke, the new oral anticoagulants had similar efficacy to warfarin  Reduced ischaemic stroke by two-thirds compared with placebo  Low dose regimen have a similar efficacy to warfarin for protection against all stroke or systemic embolic events.  However, they are not as effective for protection against ischaemic stroke in particular Discussion
  55. 55.   Favourable safety profile compared with warfarin  However, they were associated with an increase in gastrointestinal bleeding  Low dose regimen have a safer profile than warfarin  Consequently, they might be an appealing option for frail patients or for those who have a high risk for bleeding with full-dose anticoagulation Discussion
  56. 56.   Statistical heterogeneity across the trials-complete uniformity can show consistency in bias rather than consistency in real effects, so some heterogeneity is expected  Data from only clinical trials, which could affect the generalisability of the results- results of phase 4 surviellance Potential Limitations
  57. 57.   Antidote  Cost  Safety  Compliance  Realiability? The way ahead…
  58. 58. 1. Is this article from a peer reviewed journal? Yes(go on) No(stop) 2. Is the location of the study similar to mine so the results, if valid, apply to my practice? Yes(go on) No(stop) 3. Is the study sponsored by an organization that may influence the study design or results? Yes(pause) No(stop) 4. Will this information, if true, have a direct impact on the health of my patients, and is it something they will care about? Yes(go on) No(stop) 5. Is the problem addressed one that is common to my practice, and is the intervention Or test feasible and available to me? Yes(go on) No(stop) 6. Will this information , if true, will require me to change my current practice? Yes(go on) No(stop)
  59. 59. THANK YOU

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