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Novel Anticoagulants & Their Indications

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Radha Kachhy, MD
Duke Cardiology of Raleigh

Published in: Health & Medicine

Novel Anticoagulants & Their Indications

  1. 1. R A D H A K A C H H Y , M D F A C C D U K E C A R D I O L O G Y R A L E I G H A U G U S T 1 5 , 2 0 1 5 Novel Anticoagulants & Their Indications
  2. 2. No Disclosures
  3. 3. (novel) Oral Anticoagulation  Warfarin  Afib  Pitfalls  Novel Oral Anticoagulants  Agents  The data  Non valvular afib, Mechanical valves, DVT, PE, prophylaxis  Discontinuation  Elective, emergent  Triple therapy  Dosages
  4. 4. (novel) Oral Anticoagulation  This is to be distinguished from antiplatelet agents used with CAD  Aspirin  (clopidogrel or Plavix, prasugrel or Effient, ticagrelor or Brilinta)
  5. 5. Rising burden of atrial fibrillation Go, AS et al. JAMA. 2001;285:2370-2375
  6. 6. Atrial Fibrillation  Who gets anti-coagulated?  Persistent, paroxysmal, chronic, lone  Cardioversion  Chemical versus electrical
  7. 7. Definition and Scores for CHADS2 and CHA2DS2-VASc Stroke Risk Stratification With the CHADS2 and CHA2DS2- VASc Scores Score Adjusted stroke rate (% per y) CHADS2 CHADS2* Congestive HF 1 0 1.9 Hypertension 1 1 2.8 Age ≥75 y 1 2 4.0 Diabetes mellitus 1 3 5.9 Stroke/TIA/TE 2 4 8.5 Maximum score 6 5 12.5 CHA2DS2-VASc 6 18.2 Congestive HF 1 CHA2DS2-VASc† Hypertension 1 0 0 Age ≥75 y 2 1 1.3 Diabetes mellitus 1 2 2.2 Stroke/TIA/TE 2 3 3.2 Vascular disease (prior MI, PAD, or aortic plaque) 1 4 4.0 Age 65–74 y 1 5 6.7 Sex category (i.e., female sex) 1 6 9.8 Maximum score 9 7 9.6 8 6.7 9 15.20 cardiosource.org
  8. 8. Case  69 year old female with marked hyperlipidemia and h/o previous MI presents with incidentally noted atrial fibrillation. No history of hypertension, diabetes.  BP 131/82, HR 88 irregular  CHADS2 score  CHADS2VASC score  CHADS 2 score of 0 does not have a zero percent chance of stroke
  9. 9. Definition and Scores for CHADS2 and CHA2DS2-VASc Stroke Risk Stratification With the CHADS2 and CHA2DS2- VASc Scores Score Adjusted stroke rate (% per y) CHADS2 CHADS2* Congestive HF 1 0 1.9 Hypertension 1 1 2.8 Age ≥75 y 1 2 4.0 Diabetes mellitus 1 3 5.9 Stroke/TIA/TE 2 4 8.5 Maximum score 6 5 12.5 CHA2DS2-VASc 6 18.2 Congestive HF 1 CHA2DS2-VASc† Hypertension 1 0 0 Age ≥75 y 2 1 1.3 Diabetes mellitus 1 2 2.2 Stroke/TIA/TE 2 3 3.2 Vascular disease (prior MI, PAD, or aortic plaque) 1 4 4.0 Age 65–74 y 1 5 6.7 Sex category (i.e., female sex) 1 6 9.8 Maximum score 9 7 9.6 8 6.7 9 15.20 cardiosource.org
  10. 10. Warfarin  Pitfalls  Time to therapeutic  Drug-drug interaction  Dietary modifications  Compliance with regular INR checks Kovacs. J Am Coll Cardiol. 2015;65(13):1340-1360.
  11. 11. INR < 1.9 Equivalent to Aspirin • No difference in outcomes in patients with INR 1.5-1.9 versus < 1.5 in patients who presented with ischemic stroke Hylek, EM et al. NEJM 2003
  12. 12. CHADS2 score Gage BF et al. Am J Med 2005
  13. 13. H A S B L E D ypertension bnormal renal/liver function troke leeding history abile INR lderly rugs/alcohol Bleeding Risk Increases with Stroke Risk Marcucci M et al. The American Journal of Medicine (2014) 127, 979-986 1 point for each  >3 high risk  3.7 % risk of bleeding/ 100 person years
  14. 14. Warfarin Paradox: Use declines with increased stroke risk Piccini JP et al. Heart Rhythm 2012;9:1403–1408
  15. 15. Anti-coagulation and Fall Risk  It is estimated that an elderly person would need to fall 295 times per year to overcome benefit of being on anticoagulation (warfarin) Man-Son-Hing M et al. Arch Intern Med. 1999;159(7):677-685
  16. 16. NOAC Warfarin Rivaroxaban Dabigatran Apixaban Edoxaban
  17. 17. Usages  Stroke Prevention in Afib  Treatment of Acute DVT/ PE  Treatment of chronic DVT/ PE  Prophylaxis after orthopedic surgery
  18. 18. Dabigatron (Pradaxa)  Selective thrombin inhibitor  Approved indications  Non valvular AF  Treatment of VTE and PE  Reduce risk of recurrent VTE &PE  80% renal excretion  Dosing for AF  150 mg po bid  If CrCl 15-30 then use 75 mg bid
  19. 19. RE−LY  Dabigatran 150 mg superior to warfarin for stroke/systemic embolism; dabigatran 110 mg was non-inferior  Stroke ↓ in dabigatran 150 mg arm (p < 0.001)  Major bleeding was higher in warfarin arm compared with dabigatran 110 mg, but was similar to dabigatran 150 mg Trial design: Patients with AF were randomized to either dabigatran 110 mg, 150 mg, or open-label warfarin. Patients were followed for a mean of 2 years. Results Conclusions Connolly SJ, et al. N Engl J Med 2009;Aug 30. Stroke/systemic embolism • Dabigatran 150 mg superior to warfarin in reducing stroke or systemic embolism, with a similar bleeding profile. The 110 mg dose was non-inferior for efficacy, associated with lower bleeding compared with warfarin • Could prove to be alternative to warfarin for chronic anticoagulation; further data are awaited 0 5 %/year 1.53 1.11 2.71 3.11 5 10 Major bleeding 10 1.69 Dabigatran 110 mg Dabigatran 150 mg Warfarin 0 %/year 3.36 (p <0.001*, p = 0.34†) (p = 0.31*, p = 0.03†) *Dabigatran 150 mg vs. warfarin; †Dabigatran 110 mg vs. warfarin
  20. 20. Connolly SJ et al. N Engl J Med 2009;361:1139-1151. Re-ly: Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism, According to Treatment Group.
  21. 21. Re- ALIGN  RE-ALIGN is the first randomized study comparing a novel oral anticoagulant with warfarin in patients with a mechanical valve  Dabigatran is not as effective as warfarin for prevention of thromboembolic complications in patients with mechanical heart valves and is associated with more bleeding  Dabigatran should not be prescribed in patients with mechanical heart valves Eikelboom, NEJM.2013; 369: 1206-1214
  22. 22. Rivaroxaban (Xarelto)  Selective Xa inhibitor  Approved indications  Non valvular AF  Treatment of VTE and PE  Reduce risk of recurrent VTE &PE  VTE prophylaxis (hip/knee)  66% renal excretion
  23. 23. Rivaroxaban (Xarelto)  Dosing for Afib  20 mg daily with food  CrCl 15-50 use 15 mg daily  VTE treatment  15 mg po bid for 21 days and then 20 mg daily  Recurrent VTE  20 mg daily  VTE prophy  10 mg daily for 35 days after hip surgery & 12 days after knee surgery
  24. 24. 0 2 4 primary  Stroke or non-CNS systemic embolism (per 100 patient-years): 1.7 with rivaroxaban vs. 2.2 with warfarin (p for noninferiority < 0.001, p for superiority = 0.12 by intention to treat analysis, p for superiority = 0.015 by on-treatment analysis)  Major and nonmajor clinically relevant bleeding (per 100 patient-years): 14.9 vs. 14.5 (p = 0.44)  Intracranial hemorrhage (per 100 patient- years): 0.5 vs. 0.7 (p = 0.019) ROCKET AF Trial design: Patients with atrial fibrillation at increased risk for stroke were randomized to the direct factor Xa inhibitor rivaroxaban 20 mg oral daily (n = 7,131) vs. warfarin with target INR 2-3 (n = 7,133). Results Conclusions • Among atrial fibrillation patients with high stroke risk, rivaroxaban was noninferior to warfarin • Rivaroxaban (on-treatment analysis) was associated with a reduced incidence of the primary outcome without an excess of major bleeding or intracranial hemorrhage Patel MR, et al. N Engl J Med 2011;Aug 10:[Epub] (p for non- inferiority < 0.001) Rivaroxaban, 20 mg daily Per100patient- years 1.7 2.2 Stroke or non-CNS systemic embolism Warfarin, INR 2-3
  25. 25. Apixaban (Eliquis)  Selective Xa inhibitor  Approved indications  Non valvular AF  Treatment of VTE and PE  Reduce risk of recurrent VTE &PE  VTE prophylaxis (hip/knee)  FDA approved for non valvular AF for patients on hemodialysis  75% biliary excretion
  26. 26. Apixaban (Eliquis)  Afib  5 mg BID  2.5 mg bid for 2 of 3 high risk criteria: age >80, wt<60 kg, Cr>1.5  VTE treatment  10 mg po bid for 7 days then 5 mg po bid  2.5 mg po bid for recurrent VTE  VTE prophy  2.5 mg bid for 35 days after hip surgery & 12 days after knee surgery
  27. 27. Granger CB et al. N Engl J Med 2011;365:981-992. Kaplan–Meier Curves for the Primary Efficacy and Safety Outcomes.
  28. 28. Edoxaban (Savaysa)  Selective Xa inhibitor  Approved indications  Non valvular AF  Treatment of VTE and PE after 5-10 days of treatment with parenteral anticoagulant  Dosing  Afib: Cr Cl>50 then 60 mg daily  Cr Cl 15-50 then 30 mg daily  Do not use if Cr Cl>95  ENGAGE AF TIMI 48- 2013
  29. 29. ENGAGE AF-TIMI 48 ARISTOTLE ROCKET AF RE-LY Combined Favors NOAC Favors Warfarin 0.88 (0.75 - 1.02) 0.80 (0.67 - 0.95) 0.88 (0.75 - 1.03) 0.66 (0.53 - 0.82) 0.81 (0.73 - 0.91) Risk Ratio (95% CI) p=<0.0001 0.5 1 2 All NOACS: Stroke or SEE [Random Effects Model] N=58,541 Heterogeneity p=0.13 [60 mg] [150 mg] Ruff CT, et al. Lancet 2013 29
  30. 30. All-Cause Mortality MI Hemorrhagic Stroke Ischemic Stroke 0.90 (0.85 - 0.95) 0.97 (0.78 - 1.20) 0.49 (0.38 - 0.64) 0.92 (0.83 - 1.02) Risk Ratio (95% CI) p=0.0003 p=0.77 p<0.0001 p=0.10 Favors NOAC Favors Warfarin 0.2 0.5 1 2 Secondary Efficacy Outcomes Heterogeneity p=NS for all outcomes Ruff CT, et al. Lancet 2013
  31. 31. ARISTOTLE ROCKET AF Combined Favors NOAC Favors Warfarin Risk Ratio (95% CI) 0.80 (0.71 - 0.90) 0.71 (0.61 - 0.81) 1.03 (0.90 - 1.18) 0.94 (0.82 - 1.07) 0.86 (0.73 - 1.00) 0.5 1 2 All NOACS: Major Bleeding [Random Effects Model] N=58,498 p=0.06 Heterogeneity p=0.001 RE-LY [150 mg] ENGAGE AF-TIMI 48 [60 mg] Ruff CT, et al. Lancet 2013
  32. 32. GI Bleeding ICH 1.25 (1.01 - 1.55) 0.48 (0.39 - 0.59) Risk Ratio (95% CI) p=0.043 p<0.0001 Favors NOAC Favors Warfarin 0.2 0.5 1 2 Secondary Safety Outcomes Heterogeneity ICH, p=0.22 GI Bleeding, p=0.009 Ruff CT, et al. Lancet 2013
  33. 33. Advantages  Fixed dosing  No bridging  No INR monitoring  No food restrictions and fewer drug interactions
  34. 34. Disadvantages  Triple therapy  Lack of antidote & difficult to manage bleeding  Difficult to determine patient compliance  Cost  Some monitoring required: CBC/ Chem 7/ LFT/ PT/PTT at initiation and at least 1x per year
  35. 35. Triple Therapy Kovacs. J Am Coll Cardiol. 2015;65(13):1340-1360.
  36. 36. Drug Mechanism Time to peak effect Elimination ½ time warfarin Inhibition of Vit. K factors 5-7 days 5 days dabigatran Direct Thrombin Inhibitor 2-3 hrs 12-14 hrs rivaroxaban Factor Xa inhibitor 2-4 hrs 9-13 hrs apixaban Factor Xa inhibitor 1-3 hrs 8-15 hrs edoxaban Factor Xa inhibitor 1-3 hrs 10-14 hrs
  37. 37. Dabigatron Rivaroxaban Apixaban CrCl>= 50: d/c 1- 2 days prior to stand risk procedure and 3- 5 days before high risk procedure D/c 24 hours before surgery d/c 48 hours prior to stand surgery and 24 hours prior to low risk surgery CR Cl<50:d/c 3-5 days prior to stand risk procedure and >5 days before high risk procedure d/c 48 hours prior to standard risk surgery and 72 hours prior to high risk surgery Pre-procedure Use
  38. 38. Copyright © The American College of Cardiology. All rights reserved. From: Practical Management of Anticoagulation in Patients With Atrial Fibrillation J Am Coll Cardiol. 2015;65(13):1340-1360 Acute Management of Bleeding in a Patient Receiving Oral Anticoagulation
  39. 39. Switching agents  If transitioning from warfarin to NOAC  Wait until INR <2  If transitioning from one oral agent to another then dose according to when next dose is due  Example: rivaroxaban to apixaban Kovacs. J Am Coll Cardiol. 2015;65(13):1340-1360.
  40. 40. Drug interactions  P-gp inhibitors  Daibgatron, rivaroxaban, apixaban  CYP3A4 inhibitors  rivaroxaban, apixaban  Avoid with  -azole medications (reduce dose with apixaban)  Protease inhibitors  Carbamazepine  Phenytoin  Rifampin  St. John’s Wort Kovacs. J Am Coll Cardiol. 2015;65(13):1340-1360
  41. 41. Risk-Based Antithrombotic Therapy Recommendations COR LOE In patients with AF, antithrombotic therapy should be individualized based on shared decision making after discussion of the absolute risks and RRs of stroke and bleeding and the patient’s values and preferences. I C Selection of antithrombotic therapy should be based on the risk of thromboembolism irrespective of whether the AF pattern is paroxysmal, persistent, or permanent. I B In patients with nonvalvular AF, the CHA2DS2-VASc* score is recommended for assessment of stroke risk. I B For patients with AF who have mechanical heart valves, warfarin is recommended, and the target INR intensity (2.0 to 3.0 or 2.5 to 3.5) should be based on the type and location of the prosthesis. I B *CHA2DS2-VASc indicates Congestive heart failure, Hypertension, Age ≥75 years (doubled), Diabetes mellitus, Prior Stroke or TIA or thromboembolism (doubled), Vascular disease, Age 65 to 74 years, Sex category. www.cardiosource.org AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation. ACC/ AHA. 2014
  42. 42. Risk-Based Antithrombotic Therapy (cont’d) Recommendations COR LOE For patients with nonvalvular AF with prior stroke, transient ischemic attack, or a CHA2DS2-VASc score of 2 or greater, oral anticoagulants are recommended. Options include: • warfarin (INR 2.0 TO 3.0), or I A • dabigatran, or I B • rivaroxaban, or I B • apixaban. I B Among patients treated with warfarin, the INR should be determined at least weekly during initiation of antithrombotic therapy and at least monthly when anticoagulation (INR in range) is stable. I A For patients with nonvalvular AF unable to maintain a therapeutic INR level with warfarin, use of a direct thrombin or factor Xa inhibitor (dabigatran, rivaroxaban, or apixaban) is recommended. I C Re-evaluation of the need for and choice of antithrombotic therapy at periodic intervals is recommended to reassess stroke and bleeding risks. I C www.cardiosource.org AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation. ACC/ AHA. 2014
  43. 43. Risk-Based Antithrombotic Therapy (cont’d) Recommendations COR LOE Bridging therapy with UFH or LMWH is recommended for patients with AF and a mechanical heart valve undergoing procedures that require interruption of warfarin. Decisions on bridging therapy should balance the risks of stroke and bleeding. I C For patients with AF without mechanical heart valves who require interruption of warfarin or new anticoagulants for procedures, decisions about bridging therapy (LMWH or UFH) should balance the risks of stroke and bleeding and the duration of time a patient will not be anticoagulated. I C Renal function should be evaluated before initiation of direct thrombin or factor Xa inhibitors and should be re- evaluated when clinically indicated and at least annually. I B For patients with atrial flutter, antithrombotic therapy is recommended according to the same risk profile used for AF. I C www.cardiosource.org AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation. ACC/ AHA. 2014
  44. 44. Risk-Based Antithrombotic Therapy (cont’d) Recommendations COR LOE For patients with nonvalvular AF and a CHA2DS2-VASc score of 0, it is reasonable to omit antithrombotic therapy. IIa B For patients with nonvalvular AF with a CHA2DS2-VASc score of 2 or greater and who have end-stage CKD (CrCl <15 mL/min) or are on hemodialysis, it is reasonable to prescribe warfarin (INR 2.0 to 3.0) for oral anticoagulation. IIa B For patients with nonvalvular AF and a CHA2DS2-VASc score of 1, no antithrombotic therapy or treatment with an oral anticoagulant or aspirin may be considered. IIb C For patients with nonvalvular AF and moderate-to-severe CKD with CHA2DS2-VASc scores of 2 or greater, treatment with reduced doses of direct thrombin or factor Xa inhibitors may be considered (e.g., dabigatran, rivaroxaban, or apixaban), but safety and efficacy have not been established. IIb C www.cardiosource.org AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation. ACC/ AHA. 2014
  45. 45. Risk-Based Antithrombotic Therapy (cont’d) Recommendations COR LOE In patients with AF undergoing percutaneous coronary intervention,† bare-metal stents may be considered to minimize the required duration of dual antiplatelet therapy. Anticoagulation may be interrupted at the time of the procedure to reduce the risk of bleeding at the site of peripheral arterial puncture. IIb C Following coronary revascularization (percutaneous or surgical) in patients with AF and a CHA2DS2-VASc score of 2 or greater, it may be reasonable to use clopidogrel (75 mg once daily) concurrently with oral anticoagulants but without aspirin. IIb B The direct thrombin inhibitor dabigatran and the factor Xa inhibitor rivaroxaban are not recommended in patients with AF and end-stage CKD or on dialysis because of the lack of evidence from clinical trials regarding the balance of risks and benefits. III: No Benefit C The direct thrombin inhibitor dabigatran should not be used in patients with AF and a mechanical heart valve. III: Harm B †See the 2011 percutaneous coronary intervention guideline for type of stent and duration of dual antiplatelet therapy recommendations. www.cardiosource.org AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation. ACC/ AHA. 2014

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