CASE CONFERENCE
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
• Hypertens...
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...
3/6 Neurologist's OPD
• R’t side weakness, walking shifted to left side
• Neurological Examination: fast phase to left nys...
 Atrial Fibrillation
 Epidemiology
 Antithrombotic prevention
 New oral anticoagulants
 Pharmacology
 Clinical trial...
“
”
6
 Most common sustained cardiac arrhythmia
 Affects 1% of general population and 10% of aged > 80 years
 Associated with...
8
Stroke. 1991;22:983–988.
JAMA. 2001;285:2370-237.
Prevalence expected to increase 2.5-fold by 2050
 Antithrombotic prevention is recommended when the
benefits outweigh the risk
9
Risk of
stroke and
systemic
embolism
Risk...
10
BMJ. 2011 Jan 31;342:d124. JAMA. 2001 Jun 13;285(22):2864-70.
CHADS2 Points
Congestive heart failure 1
Hypertension 1
A...
Major risk factors
 Previous stroke, TIA, or
systemic embolism
 Age ≥75 years
Clinically relevant non-major
risk factors...
12
LV=left ventricular. MI=myocardial infarction. PAD=peripheral artery disease. TIA= transient ischaemic attack
BMJ. 2011...
 Should not be used to exclude patients from OAC therapy
 Risk of ischemic stroke often higher than ICH → positive net c...
 29 RCT included 28,044 patients (mean age 71 y/o; mean follow-up 1.5 yrs)
 Compared the control, adjusted-dose warfarin...
15
Circ. Cardiovasc. Qual. Outcomes 2, 297–304 (2009)
Clin Ther 2008; 30: 1726-36.
Circ Cardiovasc Qual Outcomes. 2010;3(6...
“
”
16
17
Lancet Neurol. 2012 Dec;11(12):1066-81.
Dabigatran etexilate Rivaroxaban Apixaban
Target Thrombin (reversible) Factor Xa Factor Xa
Prodrug Yes No No
Bioavailabili...
19
RE-LY
Dabigatran in the Randomized Evaluation of Long-term Anticoagulation
Therapy trial
ROCKET-AF
Rivaroxaban Once Dai...
RE-LY ROCKET-AF ARISTOTLE
Study design PROBE (warfarin open
label, dabigatran blinded)
Double-blind, double-
dummy
Double-...
RE-LY ROCKET-AF ARISTOTLE
Study design PROBE (warfarin open
label, dabigatran blinded)
Double-blind, double-
dummy
Double-...
Characteristic RE-LY ROCKET-AF ARISTOTLE
Number of patients 18,113 14,264 18,201
Lost to follow-up (n) 20 32 69
Median Fol...
Characteristic RE-LY ROCKET-AF ARISTOTLE
Number of patients 18,113 14,264 18,201
Lost to follow-up (n) 20 32 69
Median Fol...
Outcome
Dabigatran
110 mg vs. warfarin
Dabigatran
150 mg vs. warfarin
Rivaroxaban vs.
warfarin
Apixaban vs.
warfarin
RR (9...
Outcome
Dabigatran
110 mg vs. warfarin
Dabigatran
150 mg vs. warfarin
Rivaroxaban vs.
warfarin
Apixaban vs.
warfarin
RR (9...
Outcome
Dabigatran
110 mg vs. warfarin
Dabigatran
150 mg vs. warfarin
Rivaroxaban vs.
warfarin
Apixaban vs.
warfarin
RR (9...
27
N Engl J Med 2011; 365: 883–91.
The difference between these results reflects the fact that among
patients who disconti...
 Outcomes for subgroup of patients with previous
stroke or TIA were consistent
28
Outcome
Dabigatran
110 mg vs. warfarin
...
Circulation 2012 Nov 13;126(20):2381
29
Background
• NOACs were at least noninferior to vitamin K antagonists, but a
clear...
† Given the significant heterogeneity, performed a subgroup analysis to assess
each novel drug
30
Circulation 2012 Nov 13;...
Apixaban and
dabigatran reduced
major bleeding events
Whereas neither
rivaroxaban nor
edoxaban reduced
bleeding
31
Circula...
32
Circulation 2012 Nov 13;126(20):2381
Did not find any
statistically
significant difference
between the NOACs
and warfar...
NOACs are associated with an overall clinical benefit compared
with vitamin K antagonists.
33
Circulation 2012 Nov 13;126(...
34
ACCP: American College of Chest Physicians
ACCF: American College of Cardiology Foundation
AHA: American Heart Associat...
Recommendations Class Level
In patients with a CHA2DS2-VASc score ≥2, OAC therapy with:
• adjusted-dose VKA (INR 2–3); or
...
36
CCS= Canadian Cardiovascular Society
Canadian Journal of Cardiology 28 (2012) 125–136
Recommendations Class
We suggest,...
“
”
37
38
Dabigatran (Pradaxa®) Rivaroxaban (Xarelto®) Apixaban (Eliquis®)
Dosage form U.S. 75/150 mg
衛生署 110/150 mg
10/15/20 mg ...
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...
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...
Clcr Dabigatran (Pradaxa®) Rivaroxaban (Xarelto®) Apixaban (Eliquis®)
ml/min U.S. Canadian U.S. Canadian U.S. Canadian
Nom...
42
Thrombosis. 2012;2012:108983.
Dabigatran etexilate Rivaroxaban Apixaban
P-glycoprotein
substrate
V (only prodrug) V V
L...
43
Thrombosis. 2012;2012:108983.
↓ the serum
concentration of p-gp
substrates
↑ The substrates absorption
↑ serum concentr...
 At the end of trial, patient were transition from blinded trial
therapy to the open-label use of warfarin
 Increased ra...
Conversion from warfarin
 Discontinue warfarin and initiate
 Dabigatran as soon as INR <2.0
 Rivaroxaban as soon as INR...
 Warfarin can be reversed with four-factor PCC or FFP in conjunction with
vitamin K
 Absence of a reversal agent, but th...
 The timing of preoperative discontinuation of oral
anticoagulant depends on
 Elimination half-life
 Renal function and...
48
Blood. 2012 Oct 11;120(15):2954-62.
Drug (dose)
Patient renal
function
Low bleeding risk surgery
(2 or 3 drug T1/2 betw...
Drug Low bleeding risk surgery High bleeding risk surgery
Dabigatran
Resume on day after surgery
(24 h postoperative), 150...
50
Warfarin New oral anticoagulants
Advantages
• Well-established efficacy
• Adequate efficacy/safety ratio
• Can be rever...
51
Dabigatran (Pradaxa®) Rivaroxaban (Xarelto®)
Target Thrombin (reversible) Factor Xa
Dosing in Af 110/150 mg bid 15-20 m...
 Situations preferred warfarin instead of newer
anticoagulants
 Severe renal impairment, Clcr < 30 ml/min
 TTR is well ...
3/6 Neurologist's OPD
• R’t side weakness, walking shifted to left side
• Neurological Examination: fast phase to left nys...
54
1990’s
HTN
PUD
2013/03/02
StrokeDiagnosis
Medication
Antihypertensive drug
2012/02/13
stroke
AF
Antihyperlipidemic drug...
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
...
 Risk of Af-related stroke can be estimated with the CHADS2 or
CHA2DS2VASc scores, and reduced by two-thirds with effectiv...
Thank you for your attention,
and any questions are welcomed…
57
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Novel Oral Anticoagulants for Stroke Prevention in Patients With Atrial Fibrillation

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Novel Oral Anticoagulants for Stroke Prevention in Patients With Atrial Fibrillation

  1. 1. CASE CONFERENCE
  2. 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. 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. 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. 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. “ ” 6
  7. 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. 8 Stroke. 1991;22:983–988. JAMA. 2001;285:2370-237. Prevalence expected to increase 2.5-fold by 2050
  9. 9.  Antithrombotic prevention is recommended when the benefits outweigh the risk 9 Risk of stroke and systemic embolism Risk of bleeding
  10. 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. 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. 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. 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. 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. 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. “ ” 16
  17. 17. 17 Lancet Neurol. 2012 Dec;11(12):1066-81.
  18. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 32 Circulation 2012 Nov 13;126(20):2381 Did not find any statistically significant difference between the NOACs and warfarin
  33. 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. 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. 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. 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. “ ” 37
  38. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 57. Thank you for your attention, and any questions are welcomed… 57

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