Anticoagulation in atrial fibrillation

Antithrombotics in AF according to guideline

1. Anticoagulation in Atrial Fibrillation DR. MD. MASHIUL ALAM Resident University Cardiac Center Chairperson: Prof. F. Rahman

2. Atrial fibrillation Irregular, ineffective atrial contraction Worsens over time, leads to atrial remodeling 1 Slow but steady progression to chronic AF after initial paroxysmal AF 2 1. Allessie M et al. Cardiovascular Research 2002;54(2):230-246. 2. Kerr CR et al. Am Heart J 2005;149(3):489-496.

3. Atrial fibrillation: Epidemiology Affects about 1% of population - about 350,000 Canadians 1,2 Most common cardiac arrhythmia requiring medical care 1 Lifetime risk 1 in 4 for age ≥ 40 years 3 Prevalence increases with age; hence increasing due to increasingly elderly population 2 1. Go As. et al. JAMA 2001;285(18):2370-2375. 2. Brembilla -Perrot B et al.. Pacing and Clinical Electrophysiology 2004;27(3):287-292. 3. Lloyd-Jones DM et al. Circulation 2004;110(9):1042-1046.

4. Stroke risk in AF 4-5 fold increase in stroke risk in AF; 1 in 6 strokes occurs in AF patients 1,2 Stroke risk in AF increases from 1.5% at age 50-59 to 23.5% at age 80-89 1 About 40% of AF patients in primary care may be at high risk of stroke 3 1. Kannel WB et al. Am J Cardiol 1998;82(7):2N-9N. 2. Mattle HP. Cerebrovascular Diseases 2003;16(Suppl. 1):3-8. 3. Carroll K, Majeed A. Br J Gen Pract 2001;51(472):884-6, 889-91.

5. CHADS 2 score and stroke risk Risk factor Points   C - Congestive heart failure 1   H - Hypertension 1   A - Age >75 years 1   D - Diabetes 1   S - Prior  Stroke or TIA 2 CHADS 2 score Stroke rate per 100 patient-years 1.9 1 2.8 2 4.0 3 5.9 4 8.5 5 12.5 6 18.2 Gage BF et al. JAMA 2001;285(22):2864-2870.

6. CHA 2 DS 2 -VASc score Risk Factor Score C - Congestive heart failure 1 H - Hypertension 1 A - Age ≥ 75 yrs 2 D - Diabetes mellitus 1 S 2 - Prior stroke or TIA 2 V - Vascular disease 1 A - Age 65-74 years old 1 Sc - Sex category (female) 1 Lip GYH, Halperin JL. Am J Med 2010;123(6):484-488.

7. CHADS2 CHA2DS2VASc Antithrombotic therapy ASA 75-325 mg/d or preferably nothing 1 1 OAC or ASA (Preferably OAC) 2 2 OAC (INR 2-3) Initial Evaluation: CHADS2 If CHADS2 ≥ 2 -----OAC If CHADS2 < 2------CHA2DS2VASc

8. HAS-BLED score Condition Points H - Hypertension 1 A - Abnormal renal or 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 HAS-BLED score Bleeds per 100 patient-years 1.13 1 1.02 2 1.88 3 3.74 4 8.70 5 12.5 Pisters R et al. Chest 2010;138(5):1093-1100. Note: HAS-BLED has been validated for warfarin , but not for the new anticoagulants.

9. Underutilization of anticoagulation in high risk AF patients Gladstone DJ, et al. Stroke. 2009;40:235-40. Warfarin subtherapeutic Warfarin therapeutic Single antiplatelet agent No antithrombotics Dual antiplatelet therapy In addition, only 18% of AF patients who had a previous stroke had a therapeutic INR of warfarin at the time of stroke 29% 29% 30% 10% 2%

10. Antithrombotic drugs in AF Antiplatelet : ASA P2Y12 antagonist (e.g. Clopidogrel ) Anticoagulant: Warfarin NOAC ( Debigatran , Rivaroxaban , Apixaban ) Heparin

11. Newer anticoagulants ( apixaban , dabigatran , rivaroxaban ) Quickly achieve maximal blood levels and anticoagulant effects following oral administration Absorption and elimination largely unaffected by food or other medications. Administered in fixed daily doses Anticoagulation monitoring not required Relatively short serum and receptor inhibition half-lives; anticoagulant effects diminish quickly after discontinuation Skanes AC et al. Can J Cardiol 2012;28(2):125-136.

12. Novel Oral Anticoagulants – Pharmacological Properties Characteristic Apixaban Dabigatran Rivaroxaban Target Factor Xa Factor IIa Factor Xa Prodrug No Yes No Dosing BID BID OD Bioavailability, % 50% 6.5% 80-100%* Half-life 8-15 h 12-14 h 5-13h Renal clearance (unchanged drug) 27% 85% ~33% Cmax 3-4 h 1-2 h 2-4 h Drug interactions Potent inhibitors of both CYP3A4 and P- gp P- gp inhibitors Potent inhibitors of both CYP3A4 and P- gp * When the 15mg and 20mg dose is taken with food

13. Trials Comparing New Anticoagulants vs. Warfarin ARISTOTLE 1,2 RE-LY 3 ROCKET AF 4 No. of patients 18,201 18,113 14,264 CHADS 2 score 2.1 2.1 3.5 Statistical objective Non-inferiority Non-inferiority Non-inferiority Study drugs Double-blind apixaban Two doses of double-blind dabigatran Double-blind rivaroxaban Control Double-blind warfarin (INR 2–3) Open-label warfarin (INR 2–3) Double-blind warfarin (INR 2–3) Primary Dose(s) Studied 5 mg BID 110 mg BID and 150 mg BID 20 mg OD Adjusted Dose Studied 2.5 mg BID For patient with any two of the following: - Age ≥80 years - Body weight ≤60 kg - Serum creatinine ≥1.5 mg/dl (133 µmol/l) (27% renal excretion) None (~85% renal excretion) 15 mg OD For patients with CrCl = 30-49 mL/min (~33% renal excretion) 1. Lopes RD et al , 2010 ; 2.Granger CB et al , 2011; 3. Connolly SJ et al , 2009 ; 4. Patel MR et al, 2011.

14. Comparison of new anticoagulants No head-to-head comparative studies comparing new anticoagulants with each other Different study designs and patient populations; hence indirect comparisons are difficult

15. New anticoagulants in AF CHADS 2 score HAS-BLED score CHADS 2 ≥2 CHADS 2 ≥1 Consider anticoagulation for all patients New AF patient Balance stroke risk against bleeding risk. HAS-BLED score of ≥ 3 indicates increased risk of major bleeding Consider anticoagulation for most patients

16. Starting a new oral anticoagulant in a new patient Apixaban Dabigatran Rivaroxaban Usual dosage 5 mg BID 150 mg BID 20 mg OD Take with food? - - Yes Renal impairment CrCl ≥ 30 mL /min: No dose adjustment CrCl 15-30 ml/min: Use with caution CrCl <15 ml/min: not recommended CrCl 30-50 ml/min: No dose adjustment (consider 110 mg dosage); use with caution; assess renal function at least twice a year and with changes in clinical status CrCl <30 ml/min: contraindicated CrCl 30-49 mL /min: 15 mg OD CrCl <30 ml/min: not recommended Other Age ≥75 with other risk factor(s) for bleeding: 110 mg BID; also assess renal function

17. AF with specific conditions

18. AF with CHA2DS2VASc = 0 No therapy Aspirin ASA + Clopidogrel Warfarin NOAC

19. Patient with Nonrheumatic AF For patients with AF, including with Paroxysmal AF, with low risk of stroke No therapy preferred (Grade 2B) Aspirin once daily or ASA with clopidogrel (Grade 2B)

20. AF with CHA2DS2VASc = 1 No therapy ASA ASA + Clopidogrel Warfarin NOAC

21. Patient with Nonrheumatic AF AF, including with paroxysmal AF, with score = 1 OAC (Grade 1B) Aspirin (Grade 2B) ASA + Clopidogrel (Grade 2B)

22. AF + CHA2DS2VASc ≥ 2 No therapy ASA ASA + Clopidogrel Warfarin NOAC

23. Norheumatic AF AF including paroxysmal AF at high risk of stroke OAC (Grade 1A) ASA or ASA + Clopidogrel (Grade 1B) ACC guidelines- Warfarin : IA, NOAC: IB

24. AF with high risk of stroke, ESRD or hemodialysis No therapy ASA ASA + Clopidogrel Warfarin NOAC NOAC not recommanded because of lack of evidence

25. AF + MS No therapy ASA ASA + Clopidogrel Warfarin NOAC

26. AF and MS Warfarin ( INR 2-3) (Grade 1 B) Unsuitable for warfarin (for reasons other than concerns about major bleeding)----- ASA and Clopidogrel combination therapy (Grade 1B)

27. AF + Stable IHD No therapy ASA ASA + Clopidogrel Warfarin NOAC ASA + Warfarin

28. AF + Stable IHD Adjusted dose VKA ( Warfarin ) alone rather than VKA and aspirin (Grade 2C) Recommendation is same irrespective of risk of stroke

29. AF and Intracoronary stent with high risk of stroke Aspirin ASA + Clopidogrel Warfarin + clopidogrel NOAC + ASA ASA + warfarin ASA + warfarin + clopidogrel

30. AF and Intracoronary stent with high risk of stroke During the first month after BMS or the first 3 to 6 months after DES, triple therapy recommended. (Grade 2C) After this initial period VKA plus a single antiplatelet drug (Grade 2C) After 12 months after stent placement antithrombotic therapy as for patients with AF and stable IHD.

31. AF + Intracoronary stent (low or intermediate risk) ASA ASA + Clopidogrel Warfarin + Clopidogrel NOAC + ASA ASA + warfarin ASA + warfarin + clopidogrel

32. AF + Intracoronary stent (low or intermediate risk) During the first 12 months after stent placement (BMS or DES), DAPT rather than triple therapy recommended. (Grade 2C) After 12 months antithrombotic therapy as for patiens with AF and stable IHD.

33. AF and ACS (Intermediate to high risk) ASA ASA + Clopidogrel Warfarin + Clopidogrel NOAC + ASA ASA + warfarin ASA + warfarin + clopidogrel

34. AF and ACS (Intermediate to high risk) During the first 12 months VKA plus single antiplatelet therapy rather than DAPT or triple therapy. (Grade 2C) After 12 months, antithrombotic therapy as for patients for AF and stable IHD

35. AF and ACS (low risk) ASA ASA + Clopidogrel Warfarin + Clopidogrel NOAC + ASA ASA + Warfarin ASA + Warfarin + Clopidogrel

36. AF and ACS (low risk) DAPT rather than VKA plus single antiplatelet therapy or triple therapy. (Grade 2C) After 12 months, antithrombotic therapy as for patients with AF and stable IHD.

37. AF managed with a rhythm control strategy For patients with AF being managed with a rhythm control strategy (Pharmacological or catheter ablation), antithrombotic therapy decisions follow the general risk based recommendations for patients with AF, regardless of the apparent persistence of normal sinus rhythm. (Grade 2C)

38. Patients undergoing elective cardioversion of AF Presentation greater than 48 hours or unknown Therapeutic anticoagulation regardless of score ( VKA, LMWH, debigatran ) for at least 3 weeks before cardioversion or TEE guided approach with no anticoagulation. (Grade 1B) Continue anticoagulation for at least 4 weeks after successful cardioversion (Grade 1B). After 4 weeks decisions in accordance with risk based recommendation for long term antithrombotic therapy.

39. Presentation with in 48 hours or less Start anticoagulation (LMWH or UFH or NOAC) and proceed cardioversion . (Grade 2C) After successful cardioversion , therapeutic anticoagulation for at least 4 weeks (Grade 2C) Long term anticoagulation in accordance with risk based recommendations for long term antithrombotic therapy In patient with low thromboembolic risk no anticoagulation therapy may be considered and also without the need for postcardioversion oral anticoagulaiton . ( Grade IIb , LOE: C) ACC –HRS 2014

40. Unstable AF requiring urgent cardioversion Parenteral anticoagulation started before cardioversion , if possible but should not delay emergency intervation . (Grade 2C) After successful cardioversion anticoagulation for at least 4 weeks than in accordance with risk based recommendations for long term antithrombotic therapy. (Grade 2C)

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