1. Ping-Yen Liu, MD, PhD, FACC, FESC
BALANCING Risks AND BENEFITS of Novel Oral Anticoagulants: A Reappraisal Based on Current Evidence
Ping-Yen Liu, MD, PhD, FACC, FESC

2. Case #1:
A 74-year-old woman is referred to your practice for evaluation. She diagnosed with asymptomatic AF 6 months previously.
She has long history of coronary artery disease, including myocardial infarction. Absence of clinical signs or symptoms of heart failure. On examination, her heart rate is irregularly irregular at 94 bpm with a blood pressure of 120/80 mm Hg.
Laboratory tests reveal a creatinine of 0.7 mg/dl and normal liver function tests.

3. Q1-1:
Which of the following risk calculators is most useful in evaluating this patient’s risk of stroke?
CHADS2 score
CHA2DS2-VASc score
HAS-BLED score
Non of above
<PowerClick><Answer>2</Answer><Option>4</Option><Point>1</Point></PowerClick>

4. Estimation of stroke risk in AF: CHADS2
Validated using the National Registry of Atrial Fibrillation (NRAF)
Most widely used to guide the choice of antithrombotic therapy
CHADS2 risk criteria
Score
Cardiac failure 1
Hypertension
Age ≥75 yrs
Diabetes mellitus
Stroke or TIA (previous history) 2
CHADS2 Score
Stroke Risk %
1.9 1
2.8 2 4 3
5.9
8.5 5
12.5 6
18.2
TIA = transient ischaemic attack
Gage BF et al. JAMA 2001;285:2864–70

5. Risk of stroke according to CHA2DS2-VASc
CHA2DS2-VASc criteria
Score
Congestive heart failure/ left ventricular dysfunction 1
Hypertension
Age 75 years 2
Diabetes mellitus
Stroke/transient ischaemic attack/TE
Vascular disease (prior myocardial infarction, peripheral artery disease, or aortic plaque)
Age 65–74 years
Sex category (i.e. female gender)
Total score N
Adjusted stroke rate (%/year)* 1
0.0
422
1.3 2
1230
2.2 3
1730
3.2 4
1718
4.0 5
1159
6.7 6
679
9.8 7
294
9.6 8 82 9 14
15.2
*Adjusted for warfarin use. Theoretical rates without therapy; assuming that warfarin provides a 64% reduction in stroke risk, based on Hart RG et al
TE = thromboembolism
Lip G et al. Chest 2010;137:263–72; Lip G et al. Stroke 2010;41:2731–8; ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369–429; Hart RG et al. Ann Intern Med 2007;146:857–67

6. Q1-2: What antithrombotic therapy would you recommend in this patient?
Aspirin
Aspirin plus clopidogrel
Oral anticoagulation with warfarin
Oral anticoagulation with dabigatran etexilate
<PowerClick><Answer>4</Answer><Option>4</Option><Point>1</Point></PowerClick>

7. ACTIVE A: dual antiplatelet therapy superior to Aspirin alone for stroke prevention in AF
Cumulative incidence
Years
0.15
0.00 1 2 4
0.10
0.05 3
Aspirin alone Aspirin (75–100 mg/d)
Dual antiplatelet therapy
Clopidogrel (75 mg/d) + Aspirin (75–100 mg/d)
HR 0.72 (95% CI: 0.62–0.83)
P<0.0001 n=
3772
3229
2570
1203
3491
3782
3458
3155
1186
2517
Reasons for considering patients inappropriate for vitamin K antagonist included specific risk of bleeding (22.9%), physician’s judgement in absence of specific bleeding risk (49.7%) and patient preference alone (26.0%); HR = hazard ratio
ACTIVE Investigators. N Engl J Med 2009;360:2066–78
Dec 2011

8. Cumulative hazard rates
ACTIVE W: dual antiplatelet therapy inferior to oral anticoagulation for stroke prevention in AF
Stroke
Cumulative hazard rates
Years
0.05
0.00
0.5
1.0
1.5
0.04
0.03
0.02
0.01
Dual antiplatelet therapy
Clopidogrel (75 mg/d) + Aspirin (75–100 mg/d)
RR 1.72 (95% CI: 1.242.37)
P=0.001
Oral anticoagulation VKA (target INR = 2.0–3.0)
Efficacy of OAC in stroke prevention for AF patient is better than that of dual antiplatelet therapy. n=
3335
3168
2419
941 n=
3371
3232
2466
930
INR = international normalized ratio; RR = relative risk; VKA = vitamin K antagonist
ACTIVE Investigators. Lancet 2006;367:1903–12
Dec 2011

9. ACTIVE W: The treatment benefits of OAC only demonstrate when patients TTR > 65%
Connolly S J et al. Circulation 2008;118:

10. Efficacy of Aspirin in stroke prevention for AF patient is weak.
Expected number of strokes with different antithrombotic treatments in 100,000 patients with AF treated/observed for 1 year.
相較於Aspirin可再大幅降低Strokes發生率
Efficacy of Aspirin in stroke prevention for AF patient is weak.
Dabigatran 110 mg BID (1,440)
Warfarin (1,540)
Total strokes
Aspirin (3,450)
No treatment (5,998)
7000
6000
5000
4000
3000
2000
1000
No. events per patients with AF treated/observed over 1 year
Numbers of events per treatment are shown in parentheses. The length of the bars for aspirin represent the median from two trials and a metaanalysis, with dotted lines showing the range. The length of the bars for warfarin represents the median from three trials and a meta analysis.
1. Eikelboom et al. Int J Thromb Haemost doi: /j x
2. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139–51.

11. Intracranial bleeding
Expected number of fatal bleedings and intracranial bleedings and deaths with different antithrombotic treatments in 100,000 patients AF treated/observed for 1 year
Numbers of events per treatment are shown in parentheses. The length of the bars for aspirin represent the median from two trials and a metaanalysis, with dotted lines showing the range. The length of the bars for warfarin represents the median from three trials and a meta analysis.
Dabigatran 110 mg BID (190)
Warfarin(329)
Fatal bleeding
Aspirin (200)
Major bleeding and intracranial bleeding risks of Aspirin is not significantly different to that of NOAC
No treatment (153)
Dabigatran 110 mg BID (230)
Warfarin(618)
Intracranial bleeding
Aspirin (279)
No treatment (136)
Dabigatran 110 mg BID (3,750)
Warfarin (4,035)
All-cause
mortality
Aspirin (6,172)
No treatment (6,664)
7000
6000
5000
4000
3000
2000
1000
No. events per patients with AF treated/observed over 1 year
1. Eikelboom et al. Int J Thromb Haemost doi: /j x
2. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139–51.

13. 2012 ESC Guidelines for the management of atrial fibrillation
When OAC is recommended, one of the NOACs, either:
a direct thrombin inhibitor (dabigatran); or
an oral factor Xa inhibitor
should be considered rather than adjusted-
dose VKA(INR 2–3) for most patients with
nonvalvular AF, based on their net clinical benefit
Efficacy of stroke prevention with ASA is weak, with potential for harm.
Risk of major bleeding and ICH not significantly different to that of OAC, especially in the elderly
Antiplatelets for stroke prevention in AF should be limited to patients who refuse any form of OAC.
Yes
Atrial fibrillation
Valvular AF*
<65 years and lone AF (including females)
Assess risk of stroke CHA2DS2-VASc score
Assess bleeding risk (HAS-BLED score) Consider patient values and preferences
No antithrombotic therapy
Oral anticoagulant therapy
NOAC
VKA 1
No (i.e. nonvalvular) No ≥2
Antiplatelet therapy with ASA plus clopidogrel or – less effectively – ASA only, should be considered in patients who refuse any OAC or cannot tolerate anticoagulation for reasons unrelated to bleeding. If there are contraindications to OAC or antiplatelet therapy, left atrial appendage occlusion, closure or excision may be considered
Colour CHA2DS2-VASc: green = 0, blue = 1, red ≥2; line: solid = best option; dashed = alternative option
*Includes rheumatic valvular disease and prosthetic valves; ASA = acetylsalicylic acid; NOAC = novel oral anticoagulant; VKA = vitamin K antagonist
Camm AJ et al. Eur Heart J doi: /eurheartj/ehs253

14. 2012 AHA/ASA science advisory: antithrombotic therapy in AF
Recommendation
Class
Level
Dabigatran
150 mg BID: efficacious alternative to warfarin for prevention of first and recurrent stroke in patients with nonvalvular AF and ≥1 additional risk factor who have CrCl >30 mL/min I B
Rivaroxaban
20 mg/day: reasonable as an alternative to warfarin in patients with nonvalvular AF who are at moderate to high risk of stroke (prior history of TIA, stroke, or systemic embolization or ≥2 additional risk factors)
IIa
AHA = American Heart Association; ASA = American Stroke Association; BID = twice daily; CrCl = creatinine clearance; TIA = transient ischaemic attack; VKA = vitamin K antagonist
Furie KL et al. Stroke 2012;43:3442–53

15. 2012 ACCP guidelines for antithrombotic therapy in patients with AF
Patient features
Recommended antithrombotic therapy
Low risk of stroke
(e.g. CHADS2 = 0)
None (rather than antithrombotic therapy)
Intermediate risk of stroke (e.g. CHADS2 = 1)
Oral anticoagulation (rather than no therapy, Aspirin, or Aspirin + clopidogrel))
Dabigatran 150 mg BID (rather than dose-adjusted VKA*)
High risk of stroke (e.g. CHADS2 = 2)
Oral anticoagulation (rather than no therapy, Aspirin, or Aspirin + clopidogrel)
Previous stroke/TIA
BID = twice daily; TIA = transient ischaemic attack; VKA = vitamin K antagonist *Target range for international normalized ratio: 2.0–3.0
You JY et al. Chest 2012;141;e531S–e575S

16. Case #2:
You are called to the hospital to evaluate a patient with new onset AF.
The patient is an 83-year-old woman with a history of hypertension, who presented with recurrent palpitations.
She denies any history of congestive heart failure, diabetes, stroke/TIA, or vascular disease. She denies any prior history of major bleeding.
She is currently on diltiazem.
On examination, her heart rate is irregularly irregular at 72 bpm and her blood pressure is 136/82 mm Hg. Her examination is otherwise unremarkable

17. Q2-1
Laboratory tests and a full history reveal no additional risk factors for bleeding in this patient.
What would you recommend for this patient? (select only 1)
Start a NOAC
Start warfarin therapy, dose-adjusted to INR 2-3
Start aspirin
Start clopidogrel
<PowerClick><Answer>1</Answer><Option>4</Option><Point>1</Point></PowerClick>

18. A2-1

19. Case #2:
CHADS2=2
CHA2DS2-VASc=3
You are called to the hospital to evaluate a patient with new onset AF.
The patient is an 83-year-old woman with a history of hypertension, who presented with recurrent palpitations.
She denies any history of congestive heart failure, diabetes, stroke/TIA, or vascular disease. She denies any prior history of major bleeding.
She is currently on diltiazem.
On examination, her heart rate is irregularly irregular at 72 bpm and her blood pressure is 136/82 mm Hg. Her examination is otherwise unremarkable

20. Q2-2
Which clinical trial information would influence your decision regarding the use of a NOAC for anticoagulation in this patient? (select only 1)
NOACs have been associated with increased major bleeding relative to warfarin therapy
NOACs have been associated with reduced intracranial bleeding relative to warfarin therapy
NOACs have been associated with reduced GI bleeding relative to warfarin therapy
Major bleeding with NOACs has not yet been adequately evaluated in randomized controlled trials
<PowerClick><Answer>2</Answer><Option>4</Option><Point>1</Point></PowerClick>

21. A2-2

22. Targets of Novel Oral Anticoagulants
Vitamin K antagonist
Direct factor Xa inhibitors:
Apixaban
Rivaroxaban
Edoxaban
Fibrin
Tissue factor/VIIa IX
IXa X
VIIIa
Thrombin
Fibrinogen Va Xa II AT
Direct thrombin inhibitors:
Dabigatran etexilate
Ximelagatran
VII
There are several molecules within the coagulation cascade that represent promising targets for novel antithrombotics.
在凝血系列步驟中有一些分子有望成為新型抗血栓藥物的作用標的。
Tecarfarin is a novel oral vitamin K antagonist. Unlike warfarin, tecarfarin is metabolized by esterases, avoiding cytochrome P450-mediated drugdrug or drugfood interactions.
Tecarfarin為新的口服維他命K拮抗劑。與warfarin不同者，tecarfarin是由酯酶(esterases)代謝，因此可避免細胞色素P450所媒介之藥物-藥物與藥物-食物的交互作用。
Factor Xa inhibitors may block factor Xa indirectly or directly.
Xa因子抑制劑可間接或直接阻斷Xa因子的作用。
Indirect factor Xa inhibitors (e.g. idraparinux and SSR ) require antithrombin as a co-factor Xa因子間接抑制劑(例如idraparinux與SSR )需要抗凝血酶(antithrombin)作為輔因子。
Direct factor Xa inhibitors (e.g. apixaban, rivaroxaban, edoxaban and betrixaban) bind to the active site of factor Xa and block the interaction with its substrates. Xa因子直接抑制劑(例如apixaban、rivaroxaban、edoxaban與betrixaban)可與Xa因子的活性位置結合，而阻斷Xa因子與其受質的交互作用。
In the final step of the coagulation pathway, thrombin converts fibrinogen to fibrin.
在凝血路徑的最後步驟，凝血酶(thrombin)將纖維蛋白原(fibrinogen)轉變為纖維蛋白(fibrin)。
Oral, direct thrombin inhibitors bind directly to thrombin, blocking its interaction with substrates and thereby preventing fibrin formation.
口服凝血酶直接抑制劑可直接與凝血酶結合，阻斷其與受質的交互作用，因而阻止纖維蛋白的形成。
Direct thrombin inhibitors include:
凝血酶直接抑制劑包括：
Dabigatran etexilate 在Dabigatran etexilate
Ximelagatran (withdrawn from all markets in 2006) Ximelagatran (於2006年全面下市)
AZD0837. AZD0837

23. Phase III AF Trials 64% 55% 62% RE-LY ROCKET-AF ARISTOTLE
Phase III clinical study
RE-LY
ROCKET-AF
ARISTOTLE
Drug
Dabigatran
Rivaroxaban
Apixaban
Dose (mg)
Freq
150, 110
BID
20 (15*) QD
5 (2.5+) N
18,113
14,266
18,206
Mean TTR in warfarin group
64%
55%
62%
#Patients with CrCl 30–49 ml/min: 15 mg rivaroxaban once daily.
+Apixaban was dosed at 5 mg twice daily, or 2.5 mg twice daily for a subset of patients with 2 or more of the following criteria: age ≥ 80 years, body weight ≤ 60 kg, serum creatinine ≥ 1.5 mg/dL (133 µmol/L).

24. * Significant differences
Primary Endpoint: Stroke and systemic embolism in RE-LY, ROCKET-AF und ARISTOTLE
- 21%*
* Significant differences

25. Ischemic and Uncertain Stroke in RE-LY, ROCKET-AF and ARISTOTLE
- 8%
* Significant differences

26. Intracranial bleeding in RE-LY, ROCKET-AF and ARISTOTLE
- 58%*
* Significant differences

27. Major bleeding in RE-LY, ROCKET-AF and ARISTOTLE
- 31%*
* Significant differences

28. Better safety profile of dabigatran in Asian population

29. Better safety profile of dabigatran in Asian population

30. The New England Journal of Medicine March 13, 2013.

31. Figure 1. Comparison of the efficacy and safety of warfarin versus dabigatran in a Danish nationwide cohort study.

32. The bleeding risks of Rivaroxaban is similar to that of warfarin in Japanese patients

33. Case #3:
A 66-year-old man is referred to your practice for evaluation. He has a history of atrial fibrillation (AF) along with a past medical history remarkable for hypertension, congestive heart failure with preserved ejection fraction, and type 2 diabetes mellitus (T2DM).
He has no prior history of transient ischemic attack (TIA), stroke, coronary artery disease (CAD), peripheral vascular disease (PVD), gastrointestinal bleed, or other major bleeding.
He is currently taking regular dose aspirin, metoprolol, lisinopril, and metformin.
On examination, his heart rate is irregularly irregular at 84 bpm with a blood pressure of 160/86 mm Hg.
Laboratory tests reveal a creatinine of 1.0 mg/dl and normal liver function tests.

34. Q3-1:
Which of the following risk calculators is most useful in evaluating this patient’s risk of bleeding with anticoagulation? (select only 1)
CHADS2 score
CHA2DS2-VASc score
HAS-BLED score
No scoring system is currently useful for evaluating risk of bleeding with anticoagulation
CHA2DS2-VASc score and HAS-BLED score
<PowerClick><Answer>3</Answer><Option>5</Option><Point>1</Point></PowerClick>

35. A3-1

36. Bleeding risk assessment with HAS-BLED
HAS-BLED risk criteria
Score
Hypertension (SBP>160mm Hg) 1
Abnormal renal or liver function (1 point each)
1 or 2
Stroke
Bleeding
Labile INRs
Elderly (e.g. age >65 yrs)
Drugs or alcohol (1 point each)
HAS-BLED total score N
Number of bleeds
Bleeds per 100 patient-yrs*
798 9
1.13 1
1286 13
1.02 2
744 14
1.88 3
187 7
3.74 4 46
8.70 5 8
12.5 6
0.0 –
INR=international normalized ratio
*P value for trend = 0.007
Pisters R et al. Chest. 2010; [Epub ahead of print];ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369–429
Dec 2011

37. eg, treating high blood pressure, stopping antiplatelet therapy, and specific to warfarin, controlling the INR to between 2.0 and 3

38. Q3-2
What best describes your evaluation of the risk versus benefits of systemic anticoagulation in this patient? (select only 1)
His risk of intracranial bleeding with anticoagulation is greater than the benefit of stroke prevention
His risk of GI bleeding with anticoagulation is greater than the benefit of stroke prevention
His risk of bleeding with anticoagulation is less than the benefit of stroke prevention
It is not possible to evaluate his risk versus the benefit of systemic anticoagulation
<PowerClick><Answer>3</Answer><Option>4</Option><Point>1</Point></PowerClick>

39. A3-2

41. Net clinical benefit of VKAs according to different scores
(95% CI)
VKA vs. no treatment
CHADS2
HAS-BLED ≤2
HAS-BLED ≥3
Score 0
–0.02 (−0.09–0.06)
0.19 (−1.39–1.77)
Score 1
0.84 (0.70–0.99)
0.56 (0.16–0.95)
Score 2–6
1.95 (1.70–2.20)
2.68 (2.33–3.04)
CHA2DS2-VASc
–0.11 (–0.20 to –0.03) …
–0.02 (–0.15–0.11)
0.25 (–0.86–1.36)
Score 2–9
1.19 (1.07–1.32)
2.21 (1.93–2.50)
Significant positive net clinical benefit in patients with a CHADS2 score of ≥1, and CHA2DS2-VASc score of ≥2
Net clinical benefit was higher in patients with a high bleeding risk (HAS-BLED ≥3)
*Net clinical benefit = (ischaemic stroke rate with no treatment – ischaemic stroke rate on treatment) – 1.5*(ICH rate on treatment – ICH rate with no treatment); ICH = intracranial haemorrhage; VKA = vitamin K antagonist Oleson JB et al. Thromb Haemost 2011; doi: /TH
Dec 2011

42. Risk after Warfarin Therapy Interruption for GI Bleeding
Thromboembolism
Recurrent GIB
HR= 0.05; 95% CI=
HR=1.32; 95% CI=
The benefits of consistent use of anticoagulant therapy often outweigh the potential risks, even higher bleeding risks

43. Net clinical benefit for warfarin and NOACs by CHA2DS2-VASc and HAS-BLED scores
Thromb Haemost 2012; 107: 584–589

44. Net clinical benefit for warfarin and NOACs by CHA2DS2-VASc and HAS-BLED scores
Thromb Haemost 2012; 107: 584–589

45. Q3-3
Now, the patient and his family express forcefully that they are not willing to start any treatment that poses a high risk.
How would you treat this patient now? (select only 1)
Start a novel oral anticoagulant (NOAC) and discontinue use of aspirin
NOAC and switch to low-dose aspirin
Start warfarin adjusted to INR of 2-3 and discontinue use of aspirin
Start warfarin adjusted to an INR of 2-3 and continue use of aspirin
Continue aspirin alone
<PowerClick><Answer>1</Answer><Option>5</Option><Point>1</Point></PowerClick>

46. A3-3

47. Q3-4
Based on your experience, which of the following is the most significant barrier to the optimal management of anticoagulation in patients with atrial fibrillation? (select only 1)
Concerns regarding bleeding with anticoagulation
Lack of reversal agents for novel therapies
Uncertainty with management of oral anticoagulant agents in patients requiring surgical procedures
Difficulty adhering to current guidelines in real-world setting
Unfamiliarity with latest guidelines
<PowerClick><Answer>0</Answer><Option>5</Option><Point>1</Point></PowerClick>

48. Q3-5
Approximately what percentage of your patients on anticoagulation are treated with a novel oral anticoagulant, such as dabigatran, rivaroxaban, or apixaban? (select only 1)
1-25%
26-50%
51- 75%
>75%
<PowerClick><Answer>0</Answer><Option>5</Option><Point>1</Point></PowerClick>

49. SUMMARY AND CONCLUSIONS
Warfarin is is highly effective for stroke prevention in patients with AF if INR is maintained at 2.0 to 3.0. However, use of warfarin comes at a price of increased risk of overall bleeding. In particular, intracranial bleeding causes major morbidity and mortality.
NOACs provide a similar level of protection from strokes as warfarin but have a significantly lower incidence of intracranial bleeding. Overall, major bleeding is similar or reduced compared with warfarin.
NOACs offer another therapeutic option that has demonstrated clinically significant efficacy and improved safety compared with warfarin.

50. Practical Guide of dabigatran

51. Switching patients to dabigatran etexilate
Warfarin to dabigatran
Stop warfarin
Allow INR to fall below 2.0
Start dabigatran etexilate
Parenteral to dabigatran
Continuous infusions to dabigatran
Start dabigatran up to 2 hours before next parenteral drug dose
Start dabigatran at time of discontinuation of continuous infusion
INR = international normalized ratio
Huisman M et al. Thromb Haemost doi: /TH

52. Temporary discontinuation dabigatran for elective surgery
When to stop dabigatran etexilate:
Renal function (CrCl in mL/min)
Standard bleeding risk
High bleeding risk*
≥80
24 hours before
2 days before
≥50 to <80
1–2 days before
2–3 days before
≥30 to <50
2–3 days before (>48 hours)
4 days before
Due to the fast onset and offset of action of dabigatran etexilate no bridging therapy is required for the majority of interventions
*Types of surgery associated with a high risk of bleeding include but are not limited to cardiac surgery, neurosurgery, abdominal surgery, or surgeries involving a major organ. Other procedures such as spinal anaesthesia may require complete haemostatic function.
CrCl = creatinine clearance
Huisman M et al. Thromb Haemost doi: /TH

53. Drug drug interaction 避免併用 P-醣蛋白（P-gp）誘發劑（如rifampin） ketoconazole
dronedarone
可併用(謹慎評估病人出血風險)
Quinidine
Amiodarone
建議併用110mg
Verapamil
Pradaxa的藥物交互作用並不多, 但部分用藥需注意

54. Pradaxa 普栓達 衛福部核准適應症 適應症: 預防非瓣膜性心房纖維顫動病患發生中風與全身性栓塞
用法與用量: 110mg-150mg, b.i.d.
具出血風險者宜使用劑量為 110mg b.i.d., 例如: Age ≧ 75
中度腎功能障礙: CrCl = 30-50ml/min
體重 < 50 kg
CHADS2 ≧ 3
高出血風險患者
Pradaxa的適應症是預防非瓣膜性心房纖維顫動病患發生中風與全身性栓塞
目前Pradaxa有110及150mg兩種劑量,仿單上建議一些高出血風險族群的病人可考慮使用110mg
目前尚無資料支持重度腎功能受損(肌酸酐清除率< 30 mL/min)病患使用PRADAXA。因此Pradaxa不建議使用於此類病患

55. Pradaxa全民健康保險藥品給付規定 1. 限用於非瓣膜性心房纖維顫動病患，且須符合下列條件之一： 曾發生中風或全身性栓塞。
左心室射出分率小於40%。
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。
年齡75歲(含)以上。
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。
2. 排除標準：
病人曾有嚴重心臟瓣膜疾病。
14 天內發生中風。
收案前的6個月內發生嚴重中風。
有增加出血風險的情況。
肌酸酐清除率小於 30 mL/min。
活動性肝病和懷孕。
10/1日起, 健保價: 51 元／顆 (目前為58元 / 顆)

56. Thanks for Your Attention