This document summarizes the results of three major clinical trials that compared new oral anticoagulants to warfarin for stroke prevention in atrial fibrillation: - The RE-LY trial found that dabigatran 110mg and 150mg were as effective or more effective than warfarin in reducing stroke and systemic embolism. - The ROCKET-AF trial found that rivaroxaban was non-inferior to warfarin in reducing stroke and systemic embolism. - The ARISTOTLE trial found that apixaban was superior to warfarin in reducing stroke and systemic embolism. All three new oral anticoagulants were associated with

1. CASE CONFERENCE

2. Name 吳XX Admission date 2013/03/06
Age 83 HT 151 cm
Gender 女 BW 60 kg
BMI 26 Allergy history NKDA
Past history
• Hypertension
• Hyperlipidemia
• Old stroke without sequlae
• Persistant atrial fibrillation
• Peptic ulcer 20 yrs ago
Chief complaint
• Sudden onset of vertigo and nausea since 3/2 afternoon
• R’t side weakness, walking shifted to left side

3. 檢驗名稱 2013-03-06
WBC(10^3/μL) 8.1
RBC(10^6/μL) 4.60
Hb(g/dL) 13.9
Hct(%) 42.4
MCV(fl) 92.1
MCH(pg) 30.3
MCHC(g/dL) 32.9
RDW(%) 14.0
Plt(10^3/μL) 199
Seg(%) 69.4
Eos(%) 1.9
Baso(%) 0.3
Mono(%) 7.3
Lymph(%) 21.1
APTT(secs) 29.90
MNAPTT(secs) 32.7
PT(secs) 10.40
PT(MNPT)(secs) 10.5
檢驗名稱 2013-03-06 2013-03-07
CREA(mg/dL) 0.79
URIC(mg/dL) 4.1
eGFR 70
CHOL(mg/dL) 143
TRIG(mg/dL) 62
ALT(U/L) 34
NA(mmol/L) 147
K(mmol/L) 3.8
HbA1c(%) 5.0
HDL-C(mg/dL) 63
LDL-C(mg/dL) 78
Glucose (mg/dL) 115

4. 3/6 Neurologist's OPD
• R’t side weakness, walking shifted to left side
• Neurological Examination: fast phase to left nystagmus
brain MRI: left cerebellar infarction
→ Admitted for stroke management
3/9 Cerebellar infarction day 7
• Condition was stable, and she could walk without falling
→ Changed the aspirin to warfarin 0.5 tab QD
→ Discharged
3/2 Sudden onset of vertigo and nausea
3/13
OPD
• INR 1.42
→ Change Warfarin W1,3,5,7 0.5# W2,4,6 1# qd
3/13
OPD
• INR 6.49
→ DC Warfarin, and will add dabigatran after INR<2

5.  Atrial Fibrillation
 Epidemiology
 Antithrombotic prevention
 New oral anticoagulants
 Pharmacology
 Clinical trials
 Guideline update
 Practical aspects for implementation of the new agents
 Summary
5

6. “
”
6

7.  Most common sustained cardiac arrhythmia
 Affects 1% of general population and 10% of aged > 80 years
 Associated with a 5-fold increased risk of ischemic stroke,
2-fold increase in mortality
 Accounts for 16.5% of ischemic strokes or TIA in Taiwan
 Af-related stroke are more disabling and fatal
 Large emboli, older, more comorbidities
7
Circulation. 2004;110:1042-1046.
Circulation. 2010 Sep 14;122(11):1116-23.
Stroke 1991;22:983-8.

8. 8
Stroke. 1991;22:983–988.
JAMA. 2001;285:2370-237.
Prevalence expected to increase 2.5-fold by 2050

9.  Antithrombotic prevention is recommended when the
benefits outweigh the risk
9
Risk of
stroke and
systemic
embolism
Risk of
bleeding

10. 10
BMJ. 2011 Jan 31;342:d124. JAMA. 2001 Jun 13;285(22):2864-70.
CHADS2 Points
Congestive heart failure 1
Hypertension 1
Age ≥75 years 1
Diabetes mellitus 1
Stroke, TIA, or thromboembolism 2
Maximum score 6
Score Patients
Stroke rate(%) at
1 year (95% CI)
Risk and recommendation
0 22% 1.7 (1.5–1.9) Low: No therapy
1 31% 4.7 (4.4–5.1) Intermediate: *Oral anticoagulant or aspirin
2 23% 7.3 (6.9–7.8)
High: Oral anticoagulant
3 15% 15.5 (14.6–16.3)
4 7% 21.5 (20.0–23.2)
5 2% 19.7 (16.9–22.9)
6 0.2% 22.4 (14.6–34.3) * prefered

11. Major risk factors
 Previous stroke, TIA, or
systemic embolism
 Age ≥75 years
Clinically relevant non-major
risk factors
 Heart failure or LV systolic
dysfunction
 Hypertension
 DM
 Age 65-74 years
 Female sex
 Vascular disease
11
Eur Heart J 2012;33:1500–1510
Eur Heart J 2012; 33:2719-2747




12. 12
LV=left ventricular. MI=myocardial infarction. PAD=peripheral artery disease. TIA= transient ischaemic attack
BMJ. 2011 Jan 31;342:d124.
CHA2DS2VASc Points
Congestive heart failure/LV dysfunction 1
Hypertension 1
Age ≥75 years 2
Diabetes mellitus 1
Stroke, TIA, or thromboembolism 2
Vascular disease
(previous MI, PAD, or aortic plaque)
1
Age 65–74 years 1
Sex category (female sex) 1
Maximum score 9
Score Patients
Stroke rate(%) at
1 year (95% CI)
0 8% 0.8 (0.6–1.0)
1 12% 2.0 (1.7–2.4)
2 18% 3.7 (3.3–4.1)
3 23% 5.9 (5.5–6.3)
4 19% 9.3 (8.7–9.9)
5 12% 15.3 (14.3–16.2)
6 6% 19.7 (18.2–21.4)
7 2% 21.5 (18.7–24.6)
8 0·4% 22.4 (16.3–30.8)
9 0·1% 23.6 (10.6–52.6)
CHA2DS2-VASc score improve risk stratification at low or intermediate risk
(CHADS2 scores: 0 and 1)

13.  Should not be used to exclude patients from OAC therapy
 Risk of ischemic stroke often higher than ICH → positive net clinical benefit
13
Am J Med 2011; 124:111.
Ann Intern Med 2009; 151: 297-305.
Thromb Haemost 2011; 106: 739-49.
Clinical characteristic Points
Hypertension 1
Abnormal renal/liver function 1 or 2
Stroke 1
Bleeding tendency or predisposition 1
Labile INRs 1
Elderly (age > 65 years) 1
Drugs or alcohol 1 or 2
Maximum score 9
Score ≥3: high bleeding risk
Warrant special caution,
identify modifiable risk factors,
and close monitoring

14.  29 RCT included 28,044 patients (mean age 71 y/o; mean follow-up 1.5 yrs)
 Compared the control, adjusted-dose warfarin and antiplatelet agents
14
*Number needed to treat for 1 year to prevent 1 stroke
Comparison Trials, n Patients, n Strokes, n RRR %
NNT:
Primary
Prevention
NNT:
Secondary
Prevention
Aspirin vs Control 8 4876 488 22 111 34
Warfarin vs Control 6 2900 186 64 40 14
Warfarin vs Aspirin 12 12963 546 39 81 24
Ann Intern Med 2007; 146: 857-67.
Warfarin is more effective than aspirin for stroke prevention in Af

15. 15
Circ. Cardiovasc. Qual. Outcomes 2, 297–304 (2009)
Clin Ther 2008; 30: 1726-36.
Circ Cardiovasc Qual Outcomes. 2010;3(6):624.
Am J Cardiol. 2006;97(4):538.
Circulation 2010; 122: 1116-23.
Limitation
Slow onset, Drug and food interactions, >10-fold rates of individual
variation in dose, Narrow therapeutic index, Risk of bleeding…
Close INR monitoring
• Goal: 2-3
• Several studies have reported that a lower INR of warfarin (1.5-2)
than normally used is well tolerated and effective in Chinese patients
• A lower INR goal (1.8-2) may be considered in elderly patients who are
at high risk for a fall
True Facts
• Should be treated, but not treated
• Only 40-60% of patients who meet guideline criteria are treated
with anticoagulant (28.28% in Taiwan)
• Approximately 60-65% are within the therapeutic range

16. “
”
16

17. 17
Lancet Neurol. 2012 Dec;11(12):1066-81.

18. Dabigatran etexilate Rivaroxaban Apixaban
Target Thrombin (reversible) Factor Xa Factor Xa
Prodrug Yes No No
Bioavailability 6%, pH sensitive 66-100% (dose dependent) 60%
Plasma protein binding 35% 95% 87%
Dosing in Af 110/150 mg bid
15-20 mg qd
taken with the evening meal
5 mg bid
Onset of action 0.5–2 h 3–4 h 3–4 h
Tmax 0.5–2 h 2.5–4 h 3–4 h
Half-life 12–14 h 7–11 h 12 h
Excretion 80% Renal 2/3 liver, 1/3 renal 25% renal, 75% faecal
Routine monitoring No No No
18
Lancet Neurol. 2012 Dec;11(12):1066-81.

19. 19
RE-LY
Dabigatran in the Randomized Evaluation of Long-term Anticoagulation
Therapy trial
ROCKET-AF
Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with
Vitamin K Antagonism for Prevention of Stroke and Embolism Trial
ARISTOTLE
Apixaban for Reduction in Stroke and Other Thromboembolic Events in
Atrial Fibrillation
N Engl J Med 2011; 365: 981–92.
N Engl J Med 2011; 365: 883–91.
N Engl J Med 2009; 361:1139-1151.

20. RE-LY ROCKET-AF ARISTOTLE
Study design PROBE (warfarin open
label, dabigatran blinded)
Double-blind, double-
dummy
Double-blind, double-
dummy
Comparison Dabigatran 110 or 150 mg
bid vs. warfarin
Rivaroxaban 20 mg qd
vs. warfarin
Apixaban 5 mg bid
vs. warfarin
Initial dose
adjustment
15 mg qd if
Clcr 30–49 mL/min
2.5 mg bid for 2 or more of:
• age ≥80
• weight ≤60 kg
• Scr ≥ 1.5 mol/L
Inclusion criteria Af and at least one risk
factor for embolization†
Nonvalvular Af and
CHADS2≥ 2
Atrial fibrillation or flutter
and CHADS2≥ 1
Key exclusion
criteria
Valvular Af
Acute stroke
Clcr <30 ml/min
Valvular Af
Acute stroke
Clcr <30 ml/min
Valvular Af
Acute stroke
Scr >2.5 mg/dl or Clcr <25
ml/min
Populations
analyzed
ITT (intention-to-treat
analysis)
PPOT(per-protocol, on-
treatment analysis)
ITT (intention-to-treat
analysis)
Primary end point Stroke or systemic
embolism
Stroke or systemic
embolism
Stroke or systemic
embolism
20
†Previous stroke or TIA, LEVF< 40%, symptoms of heart failure, age ≥75 years or 65–74 years plus DM, HTN, or CAD

21. RE-LY ROCKET-AF ARISTOTLE
Study design PROBE (warfarin open
label, dabigatran blinded)
Double-blind, double-
dummy
Double-blind, double-
dummy
Comparison Dabigatran 110 or 150 mg
bid vs. warfarin
Rivaroxaban 20 mg qd
vs. warfarin
Apixaban 5 mg bid
vs. warfarin
Initial dose
adjustment
15 mg qd if
Clcr 30–49 mL/min
2.5 mg bid for 2 or more of:
• age ≥80
• weight ≤60 kg
• Scr ≥ 1.5 mol/L
Inclusion criteria Af and at least one risk
factor for embolization†
Nonvalvular Af and
CHADS2≥ 2
Atrial fibrillation or flutter
and CHADS2≥ 1
Key exclusion
criteria
Valvular Af
Acute stroke
Clcr <30 ml/min
Valvular Af
Acute stroke
Clcr <30 ml/min
Valvular Af
Acute stroke
Scr >2.5 mg/dl or Clcr <25
ml/min
Populations
analyzed
ITT (intention-to-treat
analysis)
PPOT(per-protocol, on-
treatment analysis)
ITT (intention-to-treat
analysis)
Primary end point Stroke or systemic
embolism
Stroke or systemic
embolism
Stroke or systemic
embolism
21
†Previous stroke or TIA, LEVF< 40%, symptoms of heart failure, age ≥75 years or 65–74 years plus DM, HTN, or CAD
Why PPOT?
• For superiority trials, ITT is considered the primary analysis population to avoid
the over-optimistic estimates of efficacy that results from a per-protocol
population
• In noninferiority trials, both ITT and PPOT analysis are recommended
• Noninferiority is best established when patients are actually taking the
randomized treatment
“ Anticipated that some patients would discontinue the study treatment. Thus, the
primary analysis was performed in the per-protocol population.”

22. Characteristic RE-LY ROCKET-AF ARISTOTLE
Number of patients 18,113 14,264 18,201
Lost to follow-up (n) 20 32 69
Median Follow-up (years) 2 1.9 1.8
CHADS2 score (mean) 2.1 3.5 2.1
0 or 1 31.9% 0 33.9%
2 35.6% 13.0% 35.8%
3-6 32.5% 86.9% 30.2%
Age (years) 71 (mean) 73 (median) 70 (median)
Female sex (%) 36 40 35
Previous stroke or TIA (%) 20 55 19
Aspirin use (%) 40 37 31
Mean TTR for warfarin (%) 64 55 62
Creatinine clearance
≤30 ml/min 0 0 1.5%
30–50 ml/min 19.4% 20.7% 18.1%
>50 ml/min 80.6% 79.6% 82.9%
22

23. Characteristic RE-LY ROCKET-AF ARISTOTLE
Number of patients 18,113 14,264 18,201
Lost to follow-up (n) 20 32 69
Median Follow-up (years) 2 1.9 1.8
CHADS2 score (mean) 2.1 3.5 2.1
0 or 1 31.9% 0 33.9%
2 35.6% 13.0% 35.8%
3-6 32.5% 86.9% 30.2%
Age (years) 71 (mean) 73 (median) 70 (median)
Female sex (%) 36 40 35
Previous stroke or TIA (%) 20 55 19
Aspirin use (%) 40 37 31
Mean TTR for warfarin (%) 64 55 62
Creatinine clearance
≤30 ml/min 0 0 1.5%
30–50 ml/min 19.4% 20.7% 18.1%
>50 ml/min 80.6% 79.6% 82.9%
23
The study population in
ROCKET-AF was at high
risk of stroke
Percentage of time in therapeutic range (TTR)
• Quality of INR control
• TTR negatively correlated with risk of
stroke, major bleeding and mortality
• Benefit from warfarin is greatest when the
TTR > 60%
• Lower TTR in ROCKET-AF: more coexisting
illnesses in high risk patient
Clcr <30 ml/min excluded Clcr <25 ml/min excluded

24. Outcome
Dabigatran
110 mg vs. warfarin
Dabigatran
150 mg vs. warfarin
Rivaroxaban vs.
warfarin
Apixaban vs.
warfarin
RR (95% CI) RR (95% CI) HR (95% CI) HR (95% CI)
Stroke or systemic embolism 0.90 (0.74–1.10) 0.65 (0.52–0.81)
PPOT 0.79 (0.66-0.96)
ITT 0.88 (0.75-1.03)
0.79 (0.66–0.95)
Ischemic stroke 1.11 (0.88–1.39) 0.76 (0.59–0.97) NA 0.92 (0.74–1.13)
Hemorrhagic stroke 0.31 (0.17–0.56) 0.26 (0.14–0.49) 0.59 (0.37–0.93) 0.51 (0.35–0.75)
Major bleeding 0.80 (0.70–0.93) 0.93 (0.81–1.07) 1.04 (0.90–1.20) 0.69 (0.60–0.80)
Intracranial hemorrhage 0.30 (0.19–0.45) 0.41 (0.28–0.60) 0.67 (0.47–0.93) 0.42 (0.30–0.58)
All-cause mortality 0.91 (0.80–1.03) 0.88 (0.77–1.00) 0.92 (0.82–1.03) 0.89 (0.80–0.99)
Myocardial infarction 1.29 (0.96–1.75) 1.27 (0.94–1.71) 0.81 (0.63–1.06) 0.88 (0.66–1.17)
Gastrointestinal bleeding 1.08 (0.85–1.38) 1.48 (1.18–1.85) NA 0.89 (0.70–1.15)
24
• Increase in MI was reported with both doses of dabigatran
• Not statistically significant, and outweigh the risk of stroke or
systemic embolism

25. Outcome
Dabigatran
110 mg vs. warfarin
Dabigatran
150 mg vs. warfarin
Rivaroxaban vs.
warfarin
Apixaban vs.
warfarin
RR (95% CI) RR (95% CI) HR (95% CI) HR (95% CI)
Stroke or systemic embolism 0.90 (0.74–1.10) 0.65 (0.52–0.81)
PPOT 0.79 (0.66-0.96)
ITT 0.88 (0.75-1.03)
0.79 (0.66–0.95)
Ischemic stroke 1.11 (0.88–1.39) 0.76 (0.59–0.97) NA 0.92 (0.74–1.13)
Hemorrhagic stroke 0.31 (0.17–0.56) 0.26 (0.14–0.49) 0.59 (0.37–0.93) 0.51 (0.35–0.75)
Major bleeding 0.80 (0.70–0.93) 0.93 (0.81–1.07) 1.04 (0.90–1.20) 0.69 (0.60–0.80)
Intracranial hemorrhage 0.30 (0.19–0.45) 0.41 (0.28–0.60) 0.67 (0.47–0.93) 0.42 (0.30–0.58)
All-cause mortality 0.91 (0.80–1.03) 0.88 (0.77–1.00) 0.92 (0.82–1.03) 0.89 (0.80–0.99)
Myocardial infarction 1.29 (0.96–1.75) 1.27 (0.94–1.71) 0.81 (0.63–1.06) 0.88 (0.66–1.17)
Gastrointestinal bleeding 1.08 (0.85–1.38) 1.48 (1.18–1.85) NA 0.89 (0.70–1.15)
25
Risk of bleeding in in older and younger patients
Major
bleeding
Dabigatran 110 mg vs Warfarin
(n=12,037)
Dabigatran 150 mg vs Warfarin
(n=12,098)
RR (95% CI) RR (95% CI)
Age <75 y 0.62 (0.50–0.77) 0.70 (0.57–0.86)
Age ≥75 y 1.01 (0.83–1.23) P <0.001 1.18 (0.98–1.42) P <0.001
Both doses of dabigatran
significantly reduced major
bleeding compared with
warfarin in patients <75 years

26. Outcome
Dabigatran
110 mg vs. warfarin
Dabigatran
150 mg vs. warfarin
Rivaroxaban vs.
warfarin
Apixaban vs.
warfarin
RR (95% CI) RR (95% CI) HR (95% CI) HR (95% CI)
Stroke or systemic embolism 0.90 (0.74–1.10) 0.65 (0.52–0.81)
PPOT 0.79 (0.66-0.96)
ITT 0.88 (0.75-1.03)
0.79 (0.66–0.95)
Ischemic stroke 1.11 (0.88–1.39) 0.76 (0.59–0.97) NA 0.92 (0.74–1.13)
Hemorrhagic stroke 0.31 (0.17–0.56) 0.26 (0.14–0.49) 0.59 (0.37–0.93) 0.51 (0.35–0.75)
Major bleeding 0.80 (0.70–0.93) 0.93 (0.81–1.07) 1.04 (0.90–1.20) 0.69 (0.60–0.80)
Intracranial hemorrhage 0.30 (0.19–0.45) 0.41 (0.28–0.60) 0.67 (0.47–0.93) 0.42 (0.30–0.58)
All-cause mortality 0.91 (0.80–1.03) 0.88 (0.77–1.00) 0.92 (0.82–1.03) 0.89 (0.80–0.99)
Myocardial infarction 1.29 (0.96–1.75) 1.27 (0.94–1.71) 0.81 (0.63–1.06) 0.88 (0.66–1.17)
Gastrointestinal bleeding 1.08 (0.85–1.38) 1.48 (1.18–1.85) NA 0.89 (0.70–1.15)
26

27. 27
N Engl J Med 2011; 365: 883–91.
The difference between these results reflects the fact that among
patients who discontinued therapy before the conclusion of the trial

28.  Outcomes for subgroup of patients with previous
stroke or TIA were consistent
28
Outcome
Dabigatran
110 mg vs. warfarin
Dabigatran
150 mg vs. warfarin
Rivaroxaban vs.
warfarin
Apixaban vs.
warfarin
RR (95% CI) RR (95% CI) HR (95% CI) HR (95% CI)
Stroke or systemic embolism 0·84 (0·58–1·20) 0·75 (0·52–1·08) 0·94 (0·77–1·16) 0·76 (0·56–1·03)
Major bleeding 0·66 (0·48–0·90) 1·01 (0·77–1·34) 0·97 (0·79–1·19) 0·73 (0·55–0·98)
Hemorrhagic stroke 0·11 (0·03–0·47) 0·27 (0·10–0·72) 0·73 (0·42–1·26) 0·37 (0·21–0·67)

29. Circulation 2012 Nov 13;126(20):2381
29
Background
• NOACs were at least noninferior to vitamin K antagonists, but a
clear superiority in overall and vascular mortality was not
consistently proven
Methods
• Meta-analysis of phase II and phase III RCT comparing NOACs (non-
VKA oral anticoagulants) with warfarin in patients with atrial
fibrillation
• NOACs: apixaban, dabigatran, edoxaban, rivaroxaban
Results
• 12 RCT enrolling a total of 54875 patients
3 involved dabigatran
4 involved rivaroxaban
2 involved apixaban
3 involved edoxaban

30. † Given the significant heterogeneity, performed a subgroup analysis to assess
each novel drug
30
Circulation 2012 Nov 13;126(20):2381
Outcome Trials Patients NOACs warfarin RR (95% CI) I2 NNT
Total mortality 12 54,115 5.61% 6.02% 0.89 (95% CI 0.83-0.96) 0% 244
Cardiovascular mortality 12 54,115 3.45% 3.65% 0.89 (95% CI 0.82-0.98) 0% 500
Stroke or systemic embolism 12 54,143 2.40% 3.13% 0.77 (95% CI 0.7 -0.86) 0% 137
Ischemic stroke 11 53,152 1.87% 2.02% 0.92 (95%CI 0.81-1.04) 22% -
Major bleeding 12 54,147 4.90% 5.54% 0.86 (95% CI 0.8 -0.93) 57% 157
Intracranial bleeding 12 54,147 0.59% 1.30% 0.46 (95% CI 0.39-0.56) 34% 141
Myocardial infarction 12 54,115 1.29% 1.29% 0.99 (95% CI 0.85-1.15) 55% -
†
†

31. Apixaban and
dabigatran reduced
major bleeding events
Whereas neither
rivaroxaban nor
edoxaban reduced
bleeding
31
Circulation 2012 Nov 13;126(20):2381

32. 32
Circulation 2012 Nov 13;126(20):2381
Did not find any
statistically
significant difference
between the NOACs
and warfarin

33. NOACs are associated with an overall clinical benefit compared
with vitamin K antagonists.
33
Circulation 2012 Nov 13;126(20):2381
Outcome Trials Patients NOACs warfarin RR (95% CI) I2 NNT
Total mortality 12 54,115 5.61% 6.02% 0.89 (95% CI 0.83-0.96) 0% 244
Cardiovascular mortality 12 54,115 3.45% 3.65% 0.89 (95% CI 0.82-0.98) 0% 500
Stroke or systemic embolism 12 54,143 2.40% 3.13% 0.77 (95% CI 0.7 -0.86) 0% 137
Ischemic stroke 11 53,152 1.87% 2.02% 0.92 (95%CI 0.81-1.04) 22% -
Major bleeding 12 54,147 4.90% 5.54% 0.86 (95% CI 0.8 -0.93) 57% 157
Intracranial bleeding 12 54,147 0.59% 1.30% 0.46 (95% CI 0.39-0.56) 34% 141
Myocardial infarction 12 54,115 1.29% 1.29% 0.99 (95% CI 0.85-1.15) 55% -
†
†

34. 34
ACCP: American College of Chest Physicians
ACCF: American College of Cardiology Foundation
AHA: American Heart Association
J Am Coll Cardiol 2011;57(11):1330-7.
Circulation. 2011;123:1144-1150
†At the time of publication, rivaroxaban and apixaban were not approved for use
ACCP 2012
 For patients with AF, including those with paroxysmal AF, for
recommendations in favor of oral anticoagulation, we suggest dabigatran
150 mg twice daily rather than adjusted-dose VKA therapy
ACCF/AHA/HRS 2011
 Dabigatran is useful as an alternative to warfarin for the prevention of
stroke and systemic thromboembolism in patients with paroxysmal to
permanent AF and risk factors for stroke or systemic embolization who do
not have a prosthetic heart valve or hemodynamically significant valve
disease, severe renal, or advanced liver disease

35. Recommendations Class Level
In patients with a CHA2DS2-VASc score ≥2, OAC therapy with:
• adjusted-dose VKA (INR 2–3); or
• a direct thrombin inhibitor (dabigatran); or
• an oral factor Xa inhibitor (e.g. rivaroxaban, apixaban)
… is recommended, unless contraindicated.
I A
In patients with a CHA2DS2-VASc score of 1, OAC therapy with:
• adjusted-dose VKA (INR 2–3); or
• a direct thrombin inhibitor (dabigatran); or
• an oral factor Xa inhibitor (e.g. rivaroxaban, apixaban)
…. should be considered, based upon an assessment of the risk of
bleeding complications and patient preferences.
IIa A
35
ESC= European Heart Rhythm Association
European Heart Journal (2012) 33, 2719–2747

36. 36
CCS= Canadian Cardiovascular Society
Canadian Journal of Cardiology 28 (2012) 125–136
Recommendations Class
We suggest, that when OAC therapy is indicated,
most patients should receive dabigatran,
rivaroxaban, or apixaban† in preference to
warfarin.
†Once approved by Health Canada
Conditional
Recommendation,
High-Quality
Evidence

37. “
”
37

38. 38
Dabigatran (Pradaxa®) Rivaroxaban (Xarelto®) Apixaban (Eliquis®)
Dosage form U.S. 75/150 mg
衛生署 110/150 mg
10/15/20 mg 2.5/5 mg
FDA labeling • Nonvalvular Af (Oct 2010) • Nonvalvular Af (Nov 2011)
• Postsurgical
prophylaxis of DVT
• DVT/PE
• Nonvalvular Af
(Dec 2012)
Not in U.S.
Labeling
• Postsurgical
prophylaxis of DVT
• Postsurgical
prophylaxis of DVT
衛生署   X
Use
 Prevention of stroke and systemic embolism in patients with nonvalvular AF
 Postoperative thromboprophylaxis in patients who have undergone hip or
knee replacement surgery
 Treatment of DVT/PE, and reduce the risk of recurrent DVT and/or PE

39. 健保規範 （ ）

1. 曾發生中風或全身性栓塞。
2. 左心室射出分率小於40%。
3. 有症狀之心臟衰竭：收案前依紐約心臟協會衰竭功能分級為第二級或以上。
4. 年齡75歲(含)以上。
5. 年齡介於65歲至74歲且合併有糖尿病、高血壓或冠狀動脈疾病。

1. 病人曾有嚴重心臟瓣膜疾病。
2. 14 天內發生中風。
3. 收案前的6個月內發生嚴重中風。
4. 有增加出血風險的情況。
5. 肌酸酐清除率小於 30 mL/min。
6. 活動性肝病和懷孕。
39

40. 健保規範 、

療 療
1. 曾發生有症狀之靜脈血栓症病史之病患；
2. 經靜脈超音波檢查（Venous ultrasonography）、靜脈攝影（Venography）或
血中D-dimer 檢測，診斷為靜脈血栓症之病患。

1. 曾發生中風或全身性栓塞。
2. 左心室射出分率小於40%。
3. 有症狀之心臟衰竭：收案前依紐約心臟協會衰竭功能分級為第二級或以上。
4. 年齡75歲(含)以上。
5. 年齡介於65歲至74歲且合併有糖尿病、高血壓或冠狀動脈疾病。
6. 排除
40

41. Clcr Dabigatran (Pradaxa®) Rivaroxaban (Xarelto®) Apixaban (Eliquis®)
ml/min U.S. Canadian U.S. Canadian U.S. Canadian
Nomal
50
30
15
25
41
150 mg
bid
150 mg
bid
15 mg
qd
15 mg
qd
2.5 mg
bid
2.5 mg
bid
75 mg
bid
20 mg
qd
20 mg
qd
5 mg
bid
5 mg
bid
AvoidAvoid AvoidAvoid Avoid Avoid
• Clcr <30 mL/min were
excluded from the RE-LY trial.
No clinical trial data for use in
patients with Clcr< 30ml/min
• 75 mg dose is based on
pharmacokinetic modeling
data

42. 42
Thrombosis. 2012;2012:108983.
Dabigatran etexilate Rivaroxaban Apixaban
P-glycoprotein
substrate
V (only prodrug) V V
Liver CYP3A4
substrate
V V
P-glycoprotein is an ATP-binding
cassette efflux transporter that extrudes
specific hydrophobic substances out of
cells into the gut

43. 43
Thrombosis. 2012;2012:108983.
↓ the serum
concentration of p-gp
substrates
↑ The substrates absorption
↑ serum concentration of p-
gp substrates
Dabigatran
• 75 mg bid in CrCl 30-50 mL/min
→Dronedarone, ketoconazole
• Avoid concurrent use
→ Rifampin
Rivaroxaban
• Avoid concurrent use
→ Ketoconazole, Itraconazole,
ritonavir, rifampin

44.  At the end of trial, patient were transition from blinded trial
therapy to the open-label use of warfarin
 Increased rate of stroke or systemic embolism in patients
transitioning from rivaroxaban than in those transitioning from
warfarin (22 vs 7; p=0.008) during the first 30 days
 Probably associated with a period of inadequate
anticoagulation during transition from rivaroxaban to warfarin.
44
Lancet Neurol. 2012 Dec;11(12):1066-81.
N Engl J Med 2011; 365: 883–91.
Emphasise the importance of the maintenance of adequate
anticoagulation in patients at high risk

45. Conversion from warfarin
 Discontinue warfarin and initiate
 Dabigatran as soon as INR <2.0
 Rivaroxaban as soon as INR to <3.0 (U.S. labeling) or ≤2.5 (Canadian labeling)
Conversion to warfarin:
 Dabigatran: Start time must be adjusted based on Clcr
 Clcr >50 mL/min: 3 days before discontinuation
 Clcr 31-50 mL/min: 2 days before discontinuation
 Clcr 15-30 mL/min: not recommended to use
 Rivaroxaban
 U.S. labeling: Initiate warfarin and a parenteral anticoagulant 24 hr after
discontinuation
 Canadian labeling: Continue rivaroxaban concomitantly with warfarin until INR
≥2.0
45

46.  Warfarin can be reversed with four-factor PCC or FFP in conjunction with
vitamin K
 Absence of a reversal agent, but the shorter half-lives provide assurance
that drug concentrations will decline relatively rapidly after discontinuation
46
British J Hematol. 2011; 154: 311-24.
Ann Pharmacother. 2011; 45:869-75.
Lancet Neurol. 2012 Dec;11(12):1066-81
Thrombosis. 2012;2012:108983.
Dabigatran (Pradaxa®) Rivaroxaban (Xarelto®) Apixaban (Eliquis®)
Half-life 12–14 h 7–11 h 12 h
Protein binding 35% 95% 87%
Management
• Local and supportive care
• Dialyzable ∼60% of
dabigatran
• Local and supportive care
• Possibly PCC, rF VIIa
• Local and supportive care
FFP= fresh frozen plasma
PCC (prothrombin complex concentrate)
• Consist of four-factor concentrates (II, VII,IX, X)
• In a small human study, PCC 50 unit/kg led immediate and complete reversal of the
anticoagulant effect of rivaroxaban

47.  The timing of preoperative discontinuation of oral
anticoagulant depends on
 Elimination half-life
 Renal function and its effect on durg elimination
 Especially with dabigatran: 80% elimination by renal
 Type of surgery and anesthesia
 Surgeries with high risk of bleeding include cardiac
surgery, neurosurgery, abdominal surgery, and spinal
anesthesia which require complete hemostasis
47
Blood. 2012 Oct 11;120(15):2954-62.

48. 48
Blood. 2012 Oct 11;120(15):2954-62.
Drug (dose)
Patient renal
function
Low bleeding risk surgery
(2 or 3 drug T1/2 between
last dose and surgery)
High bleeding risk surgery
(4 or 5 drug T1/2 between
last dose and surgery)
Dabigatran (150 mg bid)
t1/2= 14-17 h CrCl > 50 mL/min
Last dose: 2 days before surgery
(skip 2 doses)
Last dose: 3 days before surgery
(skip 4 doses)
t1/2= 16-18 h CrCl 30-50 mL/min
Last dose: 3 days before surgery
(skip 4 doses)
Last dose: 4-5 days before surgery
(skip 6-8 doses)
Rivaroxaban (20 mg qd)
t1/2= 8-9 h CrCl > 50 mL/min
Last dose: 2 days before surgery
(skip 1 dose)
Last dose: 3 days before surgery
(skip 2 doses)
t1/2= 9 h CrCl 30-50 mL/min
Last dose: 2 days before surgery
(skip 1 dose)
Last dose: 3 days before surgery
(skip 2 doses)
t1/2= 9-10 h CrCl 15-29.9 mL/min
Last dose: 3 days before surgery
(skip 2 doses)
Last dose: 4 days before surgery
(skip 3 doses)
Apixaban (5 mg bid)
t1/2= 7-8 h CrCl > 50 mL/min
Last dose: 2 days before surgery
(skip 2 doses)
Last dose: 3 days before surgery
(skip 4 doses)
t1/2= 17-18 h CrCl 30-50 mL/min
Last dose: 3 days before surgery
(skip 4 doses)
Last dose: 4 days before surgery
(skip 6 doses)

49. Drug Low bleeding risk surgery High bleeding risk surgery
Dabigatran
Resume on day after surgery
(24 h postoperative), 150 mg bid
Resume 2-3 days after surgery
(48-72 h postoperative), 150 mg bid
Rivaroxaban
Resume on day after surgery
(24 h postoperative), 20 mg qd
Resume 2-3 days after surgery
(48-72 h postoperative), 20 mg qd
Apixaban
Resume on day after surgery
(24 h postoperative), 5 mg bid
Resume 2-3 days after surgery
(48-72 h postoperative), 5 mg bid
49
Blood. 2012 Oct 11;120(15):2954-62.
Oral anticoagulants can be restarted when the patient is hemodynamically
stable and the risk of bleeding is negligible
 Factors related to resuming oral anticoagulant
 Relatively rapid onset of action, Tmax: 1-3 hours after ingestion
 Potential effect of postoperative bowel dysmotility and use of acid
suppressive therapy on drug absoption
eg. PPI, H2-blockers decrease dabigatran absorption

50. 50
Warfarin New oral anticoagulants
Advantages
• Well-established efficacy
• Adequate efficacy/safety ratio
• Can be reversed by vitamin K
• Very low cost
• Fixed dose
• No laboratory control (strong
arguable)
• Few drug interactions
• No food interactions
Disadvantages
• Slow onset of action, 3-6 days
required
• Requires frequent monitor INR
• Narrow therapeutic window
• Many drug/food interactions
• Polymorphisms
• Long half-life
• Difficult perioperative
management
• Age is an additional factor in the
risk of bleeding
• Twice-daily dosing, missing dose can
put the patient at a prothrombotic
risk (Dabigatran, apixaban)
• Dose adjustment in renal dysfunction
• Drug interactions: p-gy, CYP3A4
• No test to assess anticoagulant effect
or levels of therapeutic range
• Difficult to validate patient
compliance
• Age is an additional risk factor for
hemorrhages
• No antidote
• Gastric intolerance lead to stopping
the medication (dabigatran 21%,
rivaroxaban 23%, apixaban 25%)
• Possibility myocardial infarction
(dabigatran)Thromb J. 2011 Jul 27;9:12

51. 51
Dabigatran (Pradaxa®) Rivaroxaban (Xarelto®)
Target Thrombin (reversible) Factor Xa
Dosing in Af 110/150 mg bid 15-20 mg qd
Dosing adjustments
Patients with a higher risk of bleeding,
consider 110mg bid
• Age ≥75yr
• CHADS2 ≥ 3
• Previous GI bleed
• Clcr 30–50 mL/min: 15 mg qd
Drug interactions P-glycoprotein P-glycoprotein, CYP3A4
Contraindication
• Clcr <30 mL/min
• Hepatic enzymes >3 x ULN
• [FDA alert] Mechanical Prosthetic
Heart Valves
• Concomitant ketoconazole,
ciclosporin, itraconazole and
tacrolimus
• Clcr <30 mL/min
• Hepatic disease associated with
coagulopathy and clinically relevant
bleeding risk including cirrhotic
patients with Child Pugh B and C
• Concomitant strong CYP3A4 and P-gp
inhibitors
Safety
• Common GI adverse effects:
dyspepsia and gastritis
• Possible increased risk of MI
• Neuraxial anesthesia : epidural or
spinal hematomas syncope
Pregnancy C C
不可撥半磨粉，增加75%生體可用率，可能
造成嚴重副作用
隨餐服用，食物併服增加吸收
含有乳糖。半乳糖不耐症、Lapp乳糖酶缺乏
症或葡萄糖-半乳糖吸收不良者不應服用本藥。
健保價 NTD 116/day 98/day
• CIcr 30-50 mL/min
• Body weight <50 kg

52.  Situations preferred warfarin instead of newer
anticoagulants
 Severe renal impairment, Clcr < 30 ml/min
 TTR is well controlled under warfarin therapy
 Patients who are have concerns about compliance with
twice daily doses of dabigatran or apixaban (when
rivaroxaban unavailable)
 Who cannot afford the new anticoagulants
52

53. 3/6 Neurologist's OPD
• R’t side weakness, walking shifted to left side
• Neurological Examination: fast phase to left nystagmus
brain MRI: left cerebellar infarction
→ Admitted for stroke management
3/9 Cerebellar infarction day 7
• Condition was stable, and she could walk without falling
→ Changed the aspirin to warfarin 0.5 tab QD
→ Discharged
3/2 Sudden onset of vertigo and nausea
3/13
OPD
• INR 1.42
→ Change Warfarin W1,3,5,7 0.5# W2,4,6 1# qd
3/27
OPD
• INR 6.49
→ DC Warfarin, and will add dabigatran after INR<2

54. 54
1990’s
HTN
PUD
2013/03/02
StrokeDiagnosis
Medication
Antihypertensive drug
2012/02/13
stroke
AF
Antihyperlipidemic drugs
Aspirn
03/06
Warfarin
0.5# qd
03/13
INR 1.42
0.5#,1# qd
6.49
03/27
Dabigatran
110 mg bid
<2
CHADS2 Points
CHF
HTN 1
Age ≥75 years 1
DM
Stroke/TIA 2
Score 3
CHADS2 = 3

55. 病患衛教
 這是一種抗凝血劑，用於預防非瓣膜性心房纖維顫動病患發生中風
與全身性栓塞
 請確定身邊有足夠的藥量，以避免中斷治療而導致中風或栓塞
 須將膠囊整顆吞服，請勿弄破、研磨、咀嚼或取出膠囊內藥粒，因
可能導致藥品吸收量不穩定增加
 在進行手術、拔牙或侵入性檢查前，請主動告訴醫師您正在服用抗
凝血劑
 避免割傷自己，請小心刷牙或刮鬍鬚，盡量使用軟毛牙刷及電動刮
鬍刀
 若發生不尋常的出血現象(血尿、血便或黑便、不尋常的嚴重流鼻血
或牙齦出血出血或瘀青)，請立即就醫
 藥品該應儲存於原包裝，避免濕氣。
55

56.  Risk of Af-related stroke can be estimated with the CHADS2 or
CHA2DS2VASc scores, and reduced by two-thirds with effective
anticoagulation.
 The direct thrombin inhibitor dabigatran etexilate and factor Xa
inhibitors rivaroxaban and apixaban are new oral anticoagulants
that are at least as efficacious and safe as warfarin.
 Advantages: fixed dose, few drug interactions, no food interactions
 Disadvantages: no antidote, no test to assess anticoagulant effect,
missing dose result in inadequate anticoagulation
 Postmarketing surveillance the real-world safety and
effectiveness are needed
56

57. Thank you for your attention,
and any questions are welcomed…
57