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Atrial Fibrillation & Anticoagulants

Atrial Fibrillation & Anticoagulants. Margaret Jin, BScPhm , PharmD , MSc, CDE Hamilton Family Health Team May 27, 2014. Disclosure. I have no actual or potential conflict of interest in relation to this presentation. Outline. Case Presentation

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Atrial Fibrillation & Anticoagulants

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  1. Atrial Fibrillation & Anticoagulants Margaret Jin, BScPhm, PharmD, MSc, CDE Hamilton Family Health Team May 27, 2014

  2. Disclosure • I have no actual or potential conflict of interest in relation to this presentation

  3. Outline • Case Presentation • Canadian Cardiovascular Society 2012 Recommendations • Dabigatran (Pradaxa®) • Rivaroxaban (Xarelto®) • Apixaban(Eliquis®) • Summary • Questions

  4. Case • Mr. AF, a 70 y male with Hypertension (BP=135/85) and history of GERD. He was just diagnosed with non-valvular permanent atrial fibrillation • Normal renal and liver function • Current meds: • Ramipril 10mg once daily • Bisoprolol 5mg once daily • Amlodipine 5mg once daily • Rabeprazole 20mg once daily • No OTCs • Smokes 25 cigs/d x 55 years, drinks no alcohol • ODB drug plan BP=Blood Pressure, GERD=GastroEsophageal Reflux Disease, ODB=Ontario Drug Benefit, OTCs=Over-the-counters

  5. Anticoagulation options • What anticoagulant (if any), would you give? • None? • Aspirin? • Warfarin? • Dabigatran? • Rivaroxaban? • Apixaban?

  6. Assess Thromboembolic Therapy • Three Steps • Assess Thromboembolic Risk • CHADS2 Risk Criteria • Assess Bleeding Risk • HAS-BLED Risk Criteria • Assess Benefit vs. Risk

  7. 1. Assessing Thromboembolic Risk What is Mr. AF’s CHADS2 score?

  8. Recommended Therapy ASA=Acetylsalicylic Acid, OAC=oral anticoagulant

  9. 2. Assessing Bleeding Risk What is Mr. AF’s HAS-BLED score? ASA=acetylsalicylic acid, AST=aspartate aminotransferase, ALT=alanine aminotransferase, Hgb=hemoglobin, INRs=international normalized ratios, NSAIDS=non-steroidal anti-inflammatory drugs, SCr=serum creatinine, ULN=upper limit of normal

  10. HAS-BLED Score & Major Bleeds Major bleed Intracranial, hospitalization, decrease Hgb > 20g/L, +/- transfusion NOTE: HAS-BLED Score & Major Bleed risk is only validated with warfarin

  11. 3. Assess Risk vs. Benefit – Mr. AF • CHADS2 = 1 = 2.8%/yr Stroke rate • HAS-BLED = 1 = 1.02%/yr Major bleed • Risk of stroke > Major Bleed Risk • Recommendation: Oral anticoagulants • Warfarin • Dabigatran • Apixaban • Rivaroxaban • ODB – Limited Use for newer agents Preferred by Canadian Cardiology Society 2012 guidelines ODB=Ontario Drug Benefit

  12. Ontario Drug Benefit – Limited Use For the prevention of stroke and systemic embolism in at risk patients with non-valvular atrial fibrillation AND in whom: • Anticoagulation is inadequate{at least 35% of the tests are outside of range} following a reasonable trial{at least 3 months} of warfarin; OR • Anticoagulation with warfarin is contraindicated or not possible due to inability to regularly monitor via INR testing (i.e., No access to INR testing services at a lab, clinic, pharmacy & home)

  13. Mr. AF • Mr. AF is prescribed warfarin • 2 years later, Mr. AF’s wife died and Mr. AF is unable to cope – started drinking • INR levels fluctuating over 3 months • Time for a new oral anticoagulant • Dabigatran? (Oct 2010, LU April 2012) • Rivaroxaban? (Dec 2012, LU Aug 2013 • Apixaban? (Jan 2012, LU July 2012) LU=Limited Use

  14. Oral anticoagulants • Direct thrombin inhibitor

  15. Dabigatran • Direct thrombin inhibitor • Half-life: 12-17 hours • Dose: 150mg bid • 110mg bid if ≥ 80y or 75-79y with ≥ 1 bleeding risk factor* • Renal function • CrCl<30mL/min contraindicated • No antidote • No dosette/blisterpack or open capsule *Bleeding RF = moderate renal impairment (30-50mL/min), P-gp inhibitor, NSAID, anti-platelets, congenital/aquired coagulation disorders, thrombocytopenia or functional platelet defects, active/recent ulcerative GI bleeding, recent biopsy or major trauma, recent intracranial hemorrhage, surgery (brain, spinal or opthalmic), bacterial endocarditis

  16. Dabigatran – Drug Interactions • Contraindicated • Dronedarone, ketoconazole • Avoid: rifampicin • Increase dabigatran concentration: • P-gp inhibitors (i.e., amiodarone, clarithromycin, cyclosporine, itra-, posa-conazole, quinidine, tacagrelor, tacrolimus, verapamil, etc) • Decrease dabigatran concentration • P-gp inducers (i.e., carbamazepine, St. John’s Wort, tenofovir) • Antacids (H2RA, PPI, Al-Mg Hydroxide) H2RA=Histamine2 Receptor Antagonist, P-gp=P-glycoprotein, PPI=proton pump inhibitor, Al-Mg=aluminum-magnesium

  17. Dabigatran vs. Warfarin – RE-LY NEJM 2009;361:1139-51 • RCT, dabigatranblinded, warfarinopen-label • Intervention: • Dabigatran 150mg bid vs. dabigatran 110mg bid vs. warfarinINR 2-3 • Inclusion: AF & ≥ 1 of the following: • Previous stroke/TIA, LVEF<40, NYHA class II-IV HF within 6 months, ≥ 75y or 65-74y + DM, HTN or CAD • Exclusion: • Severe heart-valve disorder, stroke within 14 days prior or severe stroke within 6 months prior, CrCl<30mL/min, active liver disease, conditions that increase risk of bleed AF=atrial fibrillation, CAD=coronary artery disease, CrCl=creatinine clearance, DM=diabetes mellitus, HF=heart failure, HTN=hypertension, LVEF=left ventricular ejection fraction, NYHA=New York Heart Association, RCT=randomized control trial, TIA=transient ischemic attack, y=year

  18. RE-LY results NEJM 2009;361:1139-51 • N=18,113 non-valvular AF pts at risk of stroke • CHADS2 mean = 2.1 • Mean time in therapeutic range with warfarin was 64% • Median follow up = 2 years

  19. RE-LY results NEJM 2009;361:1139-51 • Dabigatran(both doses) vs. warfarin • Less hemorrhagic stroke & intracranial bleeds • More dyspepsia • Trend for higher MI? • Higher discontinuation rate with dabigatran • Dabigatran 150mg bid vs. warfarin • Superior to warfarin for stroke/SE (NNT=88) • Superior for ischemic/hemorrhagic stroke • Increase GI bleeds (NNH=100) • Dabigatran 110mg bid vs. warfarin • Non-inferior to warfarin for stroke/SE • Less major bleeds (NNT=77)

  20. Would you give Mr. AF dabigatran? • Yes, maybe? • Dabigatran 150mg bid superior to warfarin in stroke or systemic embolism • No, maybe not? • He is on a PPI – potential drug interaction – unclear about clinical significance (~14% of RE-LY study patients were on PPI) • To enhance the absorption of dabigatran, a low pH is required – dabigatran capsules contain dabigatran-coated pellets with a tartaric acid core • More GI bleed • No antidote

  21. The Hamilton Spectator • February 15, 2014 • Trials and errors? Mac, HHS sued over drug safety • In an unprecedented case, McMaster University and Hamilton Health Sciences are facing lawsuits in the United States over the safety of the drug Pradaxa. As The Spectator's Steve Buist reports, the lawsuits allege that regulatory approval for the popular anticoagulant was partly based on tainted data from clinical trials led by Hamilton researchers. http://www.thespec.com/news-story/4369907-trial-and-errors-mac-hhs-sued-over-drug-safety/

  22. Oral anticoagulants • Direct thrombin inhibitor

  23. Rivaroxaban • Direct Factor Xa Inhibitor • Half-life: 5-9h (young) or 11-13h (elderly) • Dose: 20mg once daily • CrCl 30-49mL/min: 15mg once daily • Renal function • CrCl < 30mL/min not recommended • No antidote

  24. Rivaroxaban – Drug Interactions • Contraindicated: • Itra- keto- posacon-azoles, ritonavir • CYP 3A4 and P-gp inducers (decrease rivaroxaban concentration) • Carbamazepine, clarithromycin, phenytoin, rifampin, St. John’s Wort

  25. Rivaroxaban vs. WarfarinROCKET-AF NEJM 2011;365:883-91 • RCT, double-blinded • Intervention: • Rivaroxaban 20mg od vs. warfarinINR 2-3 • Rivaroxaban 15mg od if CrCl 30-49mL/min • Inclusion: • Persistent/paroxysmal AF on ≥ 2 episodes, risk of future stroke/TIA or systemic embolism OR CHADS2 score ≥ 2 • Exclusion: • Stroke within 14 days or TIA within 3 days, anemia Hgb<100g/L, prosthetic heart valve, CrCl<30mL/min, active liver disease, conditions that increase risk of bleed AF=atrial fibrillation, CHADS2=Congestive heart failure, Hypertension, Age≥75, Diabetes, Stroke/Transient Ischemic Attack, CrCl=creatinine clearance, Hgb=Hemoglobin, RCT=randomized control trial, TIA=transient ischemic attack, y=year

  26. ROCKET-AF NEJM 2011;365:883-91 • N=14,264 non-valvular AF pts at risk of stroke • CHADS2 mean = 3.5 • Mean time in therapeutic range with warfarin was 55% (North American sites: 64%) • Median follow up per protocol = 590 days (1.6 years) • Median follow up intention-to-treat = 707 days (1.9 years)

  27. ROCKET-AF NEJM 2011;365:883-91 • Rivaroxaban vs. warfarin • Rivaroxabannon-inferior to warfarin for stroke or systemic embolism • Potential Benefits: • Less hemorrhagic stroke (NNT=333) and systemic embolism (NNT=417) • Less critical bleeding (NNT=167), less fatal bleeding (NNT=250), less intracranial bleeding (NNT=250) • Potential Harms: • More drop in Hgb ≥ 20g/L (NNH=143), more transfusions (NNH=200), more GI bleeds (NNH=100), more epistaxis (NNH=67), more hematuria (NNH=125)

  28. Would you give Mr. AF rivaroxaban? • Yes, maybe? • Rivaroxaban 20mg once daily non-inferior to warfarin in stroke or systemic embolism • Once daily dosing may be more attractive to Mr. AF • No, maybe not? • CHADS2 score = 1 • More GI bleed • No antidote

  29. Oral anticoagulants • Direct thrombin inhibitor

  30. Apixaban • Direct Factor Xa Inhibitor • Half-life: 12 hours • Dose: 5mg twice daily • 2.5mg BID if pts with ≥ 2 of the following: • Age ≥ 80, body weight ≤ 60kg, or Scr ≥ 133 umol/L • Renal function • Excluded patients with CrCl < 25mL/min • CrCl < 15mL/min not recommended • No antidote

  31. Apixaban – Drug Interactions • Contraindications • Itra- keto- posacon-azoles, ritonavir • CYP 3A4 and P-gp inducers (decrease apixaban concentration) • Carbamazepine, clarithromycin, phenytoin, rifampin, St. John’s Wort • P-gp inhibitors (increase apixaban concentration) • Amiodarone, dronedarone, quinidine, verapamil

  32. Apixaban vs. WarfarinARISTOTLE NEJM 2011;365:981-92 • RCT, double-blinded • Intervention: • Apixaban 5mg BID vs. warfarinINR 2-3 • Apixaban 2.5mg BID in pts with ≥ 2 of the following: • Age ≥ 80y, body weight ≤ 60kg, or SCr ≥ 133umol/Lmg od • Inclusion: • Permanent/persistent AF or flutter, ≥ 1 of the following stroke risk factors: age≥75y, prior stroke/TIA/systemic embolus, HF or LVEF≤40%, DM or HTN • Exclusion: • Stroke within 7 days, Hgb<90g/L, prosthetic heart valve, renal insufficiency (CrCl<25mL/min or SCr>221umol/L), active liver disease, conditions that increase risk of bleed, required ASA > 165mg/d, treatment with both ASA+thienopyridine

  33. ARISTOTLE Results NEJM 2011;365:981-92 • N=18,201 non-valvular AF pts at risk of stroke • CHADS2 mean = 2.1 • Mean time in therapeutic range with warfarin was 62.2% • Median follow-up = 1.8 years

  34. ARISTOTLE Results NEJM 2011;365:981-92 • Apixaban vs. Warfarin • Apixabansuperior to warfarin for stroke and systemic embolism (NNT=167/1.8 years) • Potential Benefits: • Decrease stroke (NNT=175), decrease hemorrhagic stroke (NNT=238) and decrease mortality (NNT=132) • Decrease major bleed (NNT=67) • Intracranial bleed (NNT=128) • Decreased d/c rates (NNT=45)

  35. Would you give Mr. AF apixaban? • Yes, maybe? • Apixaban 5mg twice daily superior to warfarin in stroke or systemic embolism • Decrease all cause mortality • No difference in GI bleeds compared to warfarin • No, maybe not? • Twice daily? • No antidote

  36. Switching FROM Warfarin NOAC • Check INR • Stop warfarin • Recheck INR in 2-4 days • Start dabigatranwhen INR < 2.0CPS • Thrombosis Canada ≤ 2.0 • Start rivaroxaban when INR ≤ 2.5CPS • Thrombosis Canada ≤ 2.0 • Start apixaban when INR < 2.0CPS • Thrombosis Canada ≤ 2.0

  37. What if? • Mr. AF’s renal function declined: • 72y male, SCr=130umol/L, Ht=65 inches, Wt=65kg, CrCl=39.5mL/min • What would you give him if he could not take warfarin? • Dabigatran 150mg or 110mg bid? • Rivaroxaban 20mg or 15mg od? • Apixaban 2.5mg or 5mg bid?

  38. Summary Warfarin advantages • 60+ years experience • Vitamin K antidote • Valvular/non-valvular AF • Allows for missed doses? • No dosage requirements for renal dysfunction • Monitoring – up to every 3 months • Cost $40/month Warfarin disadvantages • Many drug/food interactions • Slow onset • Physician/nurse/pharmacist time? • Seasonal changes in INR? • Monitoring?

  39. SummaryNovel oral anticoagulants Advantages • Less Monitoring: • SCr & CrCl at least annually • Fast onset Disadvantages • <2 years experience • No antidote • If miss dose, short half-life – quick “offset” • Renal function dose adjustments • Cost > $100/month

  40. Summary • Warfarin is preferred in: • Mechanical or valvular AF • If INR is stable on warfarin • CrCl < 30mL/min • Liver dysfunction • Poor compliance (or maybe no OAC is preferred) • Morbidly Obese?

  41. Summary • Dabigatran150mg bid preferred if recent ischemic stroke on warfarin • Rivaroxaban or apixaban is preferred: • CrCl 30-50mL/min • Dypepsia or upper GI bleed • Recent acute coronary syndrome • Apixaban preferred if recent GI bleed • Rivaroxaban preferred if poor compliance with twice daily dosing or request for a once-daily regimen

  42. Questions?

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