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

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Presentation on theme: "Atrial Fibrillation & Anticoagulants Margaret Jin, BScPhm, PharmD, MSc, CDE Hamilton Family Health Team May 27, 2014."— Presentation transcript:

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 1. Assess Thromboembolic Risk a.CHADS 2 Risk Criteria 2. Assess Bleeding Risk a.HAS-BLED Risk Criteria 3. Assess Benefit vs. Risk

7 1. Assessing Thromboembolic Risk CHADS 2 Risk CriteriaPoints Congestive Heart Failure (symptoms in the last 3 months) 1 Hypertension (diagnosis)1 Age ≥ 75 years1 Diabetes mellitus1 Stroke/Transient Ischemic Attack (prior)2 What is Mr. AF’s CHADS 2 score?

8 Recommended Therapy CHADS 2 Stroke Rate %/yr Canadian Cardiology Society (CCS) 2012 Recommendations 01.9No additional risk factors: No antithrombotic Female or vascular disease: ASA mg daily Age ≥ 65 yrs or female & vascular disease: OAC 12.8OAC preferred Alternatives: ASA mg daily 24 Oral anticoagulant (OAC) When OAC is indicated, most patients should receive dabigatran, rivaroxaban, or apixaban in preference to warfarin CCS ASA=Acetylsalicylic Acid, OAC=oral anticoagulant

9 2. Assessing Bleeding Risk HAS-BLED Risk CriteriaPoints Hypertension (SBP > 160 mmHg)1 Abnormal renal (transplantation, dialysis, SCr > 200umol/L) or liver function (AST/ALT>3xULN, bilirubin>2xULN) (1 point each) 1 to 2 Stroke (caused by a bleed)1 Bleeding (hospitalization, decrease Hgb > 20g/L, transfusion)1 Labile INRs (therapeutic range < 60%)1 Elderly (age > 65 years)1 Drugs (ASA/NSAID) or alcohol (≥8 drinks/week) (1 point each)1 to 2 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 What is Mr. AF’s HAS-BLED score?

10 HAS-BLED Score & Major Bleeds HAS-BLED Score Major Bleeds (%/yr) 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 CHADS 2 = 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: 1. Anticoagulation is inadequate {at least 35% of the tests are outside of range} following a reasonable trial {at least 3 months} of warfarin; OR 2. 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 Half-life: 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 (H 2 RA, PPI, Al-Mg Hydroxide) H 2 RA=Histamine 2 Receptor Antagonist, P-gp=P-glycoprotein, PPI=proton pump inhibitor, Al-Mg=aluminum-magnesium

17 Dabigatran vs. Warfarin – RE-LY RCT, dabigatran blinded, warfarin open-label Intervention: ◦ Dabigatran 150mg bid vs. dabigatran 110mg bid vs. warfarin INR 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 NEJM 2009;361:

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

19 RE-LY results EndpointWarfarin n=6022 Dabi 110 n=6015 Dabi 150 n=6076 NNT/H Dabi 110 NNT/H Dabi 150 Stroke/SE3.35%3.04%2.21%-88 MI1.25%1.63%1.6%-- Major bleed 6.99%5.69%6.57%77- Intracranial bleed 1.49%0.45%0.63%96116 GI bleed2.09%2.28%3.09%-100 Minor bleed 32%26%29.4%1739 Dyspepsia5.8%11.8%11.3%1718 D/C Net clinical benefit 15.5%14.5%14.1%-71 NEJM 2009;361:

20 RE-LY results 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) NEJM 2009;361:

21 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

22 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. over-drug-safety/

23 Oral anticoagulants Direct thrombin inhibitor

24 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

25 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

26 Rivaroxaban vs. Warfarin ROCKET-AF RCT, double-blinded Intervention: ◦ Rivaroxaban 20mg od vs. warfarin INR 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 CHADS 2 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 NEJM 2011;365:883-91

27 ROCKET-AF N=14,264 non-valvular AF pts at risk of stroke CHADS 2 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) NEJM 2011;365:883-91

28 ROCKET-AF Rivaroxaban vs. warfarin ◦ Rivaroxaban non-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) NEJM 2011;365:883-91

29 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? CHADS 2 score = 1 More GI bleed No antidote

30 Oral anticoagulants Direct thrombin inhibitor

31 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

32 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

33 Apixaban vs. Warfarin ARISTOTLE RCT, double-blinded Intervention: ◦ Apixaban 5mg BID vs. warfarin INR 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 221umol/L), active liver disease, conditions that increase risk of bleed, required ASA > 165mg/d, treatment with both ASA+thienopyridine NEJM 2011;365:981-92

34 ARISTOTLE Results N=18,201 non-valvular AF pts at risk of stroke CHADS 2 mean = 2.1 Mean time in therapeutic range with warfarin was 62.2% Median follow-up = 1.8 years NEJM 2011;365:981-92

35 ARISTOTLE Results Apixaban vs. Warfarin ◦ Apixaban superior 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) NEJM 2011;365:981-92

36 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

37 Switching FROM Warfarin  NOAC 1. Check INR 2. Stop warfarin 3. Recheck INR in 2-4 days Start dabigatran when INR < 2.0 CPS ◦ Thrombosis Canada ≤ 2.0 Start rivaroxaban when INR ≤ 2.5 CPS ◦ Thrombosis Canada ≤ 2.0 Start apixaban when INR < 2.0 CPS ◦ Thrombosis Canada ≤ 2.0

38 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?

39 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/pharmaci st time? Seasonal changes in INR? Monitoring?

40 Summary Novel 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

41 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?

42 Summary Dabigatran 150mg 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

43 Questions?


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