1. Management of Atrial fibrillation with NOAC (no longer novel)
Il-Young Oh, MD

2. Coronary angiography & echocardiography in patients with AF

3. The management cascade for patients with AF
Eur Heart J. 2010;31:

4. CHA2DS2VASc score and stroke rate
Risk factors for stroke and thrombo-embolism in non-valvular AF
‘Major’ risk factors
‘Clinically relevant non-major’ risk factors
Previous stroke, TIA, or systemic embolism Age ≥75 years
HF or moderate to severe LV systolic dysfunction (e.g. LV EF ≤40%), Hypertension, DM, Female sex, Age 65–74 years, Vascular disease*
Risk factor-based approach expressed as a point based scoring system, with the acronym CHA2DS2-VASc
Risk factor
Score
CHF / LV dysfunction
Hypertension
Age ≥75
Diabetes mellitus
Stroke/TIA/thrombo-embolism
Vascular disease*
Age 65–74
Sex category (i.e. female sex) 1 2
*Prior MI, PAD, aortic plaque. Actual rates of stroke in contemporary cohorts may vary from these estimates
Eur Heart J. 2010;31:

5. CHA2DS2-VASc score and stroke rate
Patients (n=1733)
Adjusted stoke rate (%/year) 1 2 3 4 5 6 7 8 9
422
1230
1730
1718
1159
679
294 82 14 0%
1.3%
2.2%
3.2%
4.0%
6.7%
9.8%
9.6%
15.2%
*CHF / LV dysfunction, Hypertension, Age ≥75 [2], Diabetes mellitus, Stroke / TIA / thrombo-embolism [2], Vascular disease, Age 65–74, Sex category (i.e. female sex)
Eur Heart J. 2010;31:

6. Warfarin
… Karl Link continued working on developing more potent coumarin-based anticoagulants for use as rodent poisons, resulting in warfarin in …(from Wikipedia)
Wisconsin Alumni Research Foundation (WARF)
Sweet clover
Sweet clover disease

7. Mechanism of action of warfarin
This inhibits vitamin K–dependent -carboxylation of factors II, VII, IX, and X because reduced vitamin K serves as a cofactor for a γ-glutamyl carboxylase that catalyzes the γ-carboxylation process, thereby converting prozymogens to zymogens capable of binding calcium and interacting with anionic phospholipid surfaces.
A racemic mixture of S- and R-enantiomers, S-warfarin is most active.
Longo DL. Harrison's principles of internal medicine. 18th ed. New York: McGraw-Hill; 2012.

8. Sites of action of the four major physiologic antithrombotic pathways
Antithrombin (or antithrombin III) is the major plasma protease inhibitor of thrombin and the other clotting factors in coagulation.
Antithrombin, the obligatory plasma cofactor for heparin, is a member of the serine protease inhibitor (serpin) superfamily.
(Factor IIa)
(Factor II)
Longo DL. Harrison's principles of internal medicine. 18th ed. New York: McGraw-Hill; 2012.

9. Oral ximelagatran for secondary prophylaxis after MI
Ximelagatran, twice daily
*All patients received 160 mg acetylsalicylic acid once daily, unless titrated downwards to 75 mg because of adverse effects perceived related to acetylsalicylic acid
Lancet. 2003;362:

10. Ximelagatran vs LMWH/VKA for DVT
Randomized, double-blind, noninferiority trial (Thrombin Inhibitor in Venous Thromboembolism [THRIVE] Treatment Study) of 2489 patients with acute DVT, of whom approximately one third had concomitant PE.
Ximelagatran, 36 mg bid
ALT [GPT] levels increased to more than 3 times the upper limit of normal in 119 patients (9.6%) and 25 patients (2.0%) receiving ximelagatran and enoxaparin/warfarin, respectively.
Retrospective analysis of locally reported adverse events showed a higher rate of serious coronary events with ximelagatran (10/1240 patients) compared with enoxaparin/warfarin (1/1249 patients).
JAMA. 2005;293:681-9.

12. Overview of design of the pivotal phase III trials of NOAC compared with warfarin in nonvalvular AF
RELY
(NEJM 2009)
ROCKET
(NEJM Sep 2011)
ARISTOTLE
ENGAGE AF
(NEJM Nov 2013)
Sample size
18,113
14,264
18,201
21,105
New treatment and dose
Dabigatran 110 mg bid
Dabigatran 150 mg bid
Rivaroxaban 20 mg qd
Apixaban 5 mg bid
Edoxaban 60 mg qd
Edoxaban 30 mg qd
Dose adjustment No
At randomization
Design
Noninferiority
PROBE
Double blinded
Patients
CHADS2 ≥1
71 years, 64% Men
CHADS2 ≥2
73 years, 60% Men
70 years, 65% Men
72 years, 62% Men
Primary outcome
Stroke or systemic embolism
Safety outcome
Major bleeding

13. meta-analysis of randomised trials with NOACs
Stroke or systemic embolic events
Major bleeding
Lancet. 2014;383:

14. Pharmacological characteristics of NOAC
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Mechanism of action
Selective direct FIIa inhibitor
Selective direct FXa inhibitor
Oral bioavailability, %
6.5
80-100 50 62
Half-life, h
12-17
5-13
8-15
6-11
Renal elimination, % 85
66 (36 unchanged and 30 inasctive metabolites) 27
Time to maximum inhibition, h
0.5-2
1-4
1-2
Potential metabolic drug interactions
Inhibitors of P-gp:verapamil, reduce dose; dronedarone: avoid
Potent inducers of P-gp: avoid
Potent inhibitors of CYP3A4 and P-gp: avoid
Potent inducers of CYP3A4 and P-gp: use with caution
Potent inducers of CYP3A4 and P-gp use with caution
Potent inhibitors of P-gp: reduce dose
CYP = cytochrome P450 isoenzyme; F = factor; P-gp = P-glycoprotein.
J Am Coll Cardiol. 2012;59:

15. Absorption and metabolism of the different new anticoagulant drugs
Europace. 2013;15:

16. Dose Selection of Oral Anticoagulant Options for Patients with Nonvalvular AF and CKD
Renal function
Warfarin
Dabigatran
Rivaroxaban
Apixaban
Normal/Mild impairment
Dose adjusted for INR
150 mg bid (CrCl >30 mL/min)
20 mg QD with the evening meal (CrCl >50 ml/min)
5.0 or 2.5 mg bid1
Moderate impairment
150 mg bid or 75 mg bid (CrCl >30 mL/min)
15 mg QD with the evening meal (CrCl ml/min)
Severe impairment
75 mg bid (CrCl mL/min)
15 mg QD with the evening meal (CrCl ml/min)
No recommendation2
End-stage CKD Not on Dialysis
Not recommended
(CrCl <15 mL/min)
End-stage CKD on Dialysis
No recommendation2-3
Use apixaban 2.5 mg BID if any 2 patient characteristics present: Cr ≥1.5 mg/dL, ≥80 years of age, body weight ≤60 kg. Apixaban is not recommended in patients with severe hepatic impairment.
No published studies support a dose for this level of renal function.
In patients with end-stage CKD on stable hemodialysis, prescribing information indicates the use of apixaban 5 mg BID with dose reduction to 2.5 mg BID if the patient is either ≥80 years of age or body weight ≤60 kg
2014 AHA/ACC/HRS AF Guideline

17. Management of bleeding associated with NOACs.
Europace [epub]

18. Idarucizumab for Dabigatran Reversal
A Phase III Case Series Clinical Study of the Reversal of the Anticoagulant Effects of Dabigatran by Intravenous Administration of 5.0g Idarucizumab in Patients Treated Wtih Dabigatran Etexilate Who Have Uncontrolled Bleeding or Require Emergency Surgery or Procedures.RE-VERSE AD (A Study of the RE-VERSal Effects of Idarucizumab on Active Dabigatran) Trial
*Idarucizumab is a humanized antibody fragment, or Fab, being investigated as a specific reversal agent for the anticoagulant effect of dabigatran in patients needing emergency surgery or urgent procedures or for life-threatening or uncontrolled bleeding events.
Interim analysis of RE-VERSE AD. N Engl J Med. 2015;373:

19. Andexanet for Reversal of Factor Xa Inhibitor Activity
Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion.
N Engl J Med. 2015;373:

20. Discontinuation of NOACs before elective procedures
BMJ. 2015;351:h2391.

21. Switching between anticoagulant regimens
From VKA to NOAC
Dabigatran – discontinue VKA and start dabigatran when the INR is <2
Rivaroxaban or apixaban – discontinue VKA and initiate rivaroxaban or apixaban when the INR falls to <3 or <2, respectively
From NOAC to VKA
Dabigatran
CrCl ≥50 mL/min/1.73 m2, start VKA 3 d before stopping dabigatran
CrCl mL/min/1.73 m2, start VKA 2 d before stopping dabigatran
CrCl mL/min/1.73 m2, start VKA 1 d before stopping dabigatran
VKA effect on INR truly reflected only after dabigatran stopped for ≥2 d)
Rivaroxaban
CrCl ≥50 mL/min/1.73 m2, start VKA 4 d before stopping rivaroxaban
CrCl mL/min/1.73 m2, start VKA 3 d before stopping rivaroxaban
CrCl mL/min/1.73 m2, start VKA 2 d before stopping rivaroxaban
VKA effect on INR truly reflected only after rivaroxaban stopped for ≥1 d
Apixaban
Continue both apixaban and VKA until INR is ≥2.0
Mayo Clinic proceedings. 2013;88:

22. Effect of Dabigatran on Point-of-care INR
INR (ratio)
aPTT (sec)
Coagulation monitoring may be advisable in some situations to identify patients at increased bleeding risk.
POC should not be used for measurement of INR in patients taking dabigatran, as levels are falsely elevated.
Laboratory-aPTT measurement is preferred to detect excess anticoagulant activity.
The American journal of medicine. 2012;125:

23. Proposed shared multidisciplinary time-table for clinical and laboratory serial FU
Int J Cardiol. 2016;202:

24. ?
2012 focused update of the ESC Guidelines for the management of AF

25. Definitions of valvular heart disease in many RCTs
RE-LY trial: ‘… history of heart valve disorders (i.e., prosthetic valve or hemodynamically relevant valve disease) … ’;
ROCKET-AF trial:… hemodynamically significant mitral valve stenosis. Prosthetic heart valve (annuloplasty with or without prosthetic ring, commissurotomy and/or valvuloplasty are permitted) …’;
ARISTOTLE trial:… moderate or severe mitral stenosis, conditions other than atrial fibrillation that required anticoagulation (e.g., a prosthetic heart valve) …’;
ENGAGE AF trial: … moderate-to severe mitral stenosis …’.

26. Valvular AF Definitions in our hospital Definitions in AHA
Rheumatic mitral valve disease
Prosthetic valve in situ, including MV plasty
Definitions in AHA
AF in the absence of rheumatic mitral stenosis, a mechanical or bioprosthetic heart valve, or mitral valve repair.
Definitions in ESC
The term valvular AF isused to imply that AF is related to rheumatic valvular disease (predominantly mitral stenosis) or prosthetic heart valves.

27. NOAC 보험기준 비판막성 심방세동 환자 중 고위험군에서 급여로 인정하고 있다. ※ 고위험군의 기준
혈전색전증(뇌졸중, 일과성허혈발작, 전신성 색전증)의 과거력이 있거나 75세 이상 환자
다음 6가지(심부전, 고혈압, 당뇨, 혈관성 질환, 65-74세, 여성) 중 2가지 이상의 조건을 가지고 있는 환자

28. 용량 프라닥사 – 75세 이상, 크레아티닌 청소율 30-49 ml/min에서는 110 mg bid
자렐토 – 크레아티닌 청소율 ml/min에서는 15 mg qd
엘리퀴스 - 80세 이상, 60 kg 이하, 혈청 크레아티닌 ≥1.5 mg/dL 중 2개 이상에서는 2.5 mg bid
릭시아나 - 크레아티닌 청소율 ml/min, 60 kg 이하, P-gp 저해제(사이클로스포린, 드로네다론, 에리트로마이신, 케토코나졸) 병용 중 1개 이상에서는 30 mg qd