Transcript New oral anticoagulants and antiplatelet use: Stroke prevention in

Update of anticoagulants use:
Stroke prevention in atrial
fibrillation
三軍總醫院
神經科部
李俊泰
Outline
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•
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Introduction
Anticoagulant in atrial fibrillation
Novel anticoagulant
Guideline
腦中風中心品質管制指標
1.
2.
3.
4.
5.
6.
7.
8.
9.
tPA的施打
吞嚥困難篩檢
住院中血脂測量
戒菸
中風衛教
復健計畫
48小時內使用抗血栓藥物
出院時使用抗血栓藥物(心房顫動病人使用抗
凝血藥物)
有系統的監控、評估照護品質與死亡率。
2007 May
心房顫動可能完全
無症狀，大部分心
悸(heart
palpitations)、呼
吸急促、虛弱和昏
厥
AF SIGNIFICANTLY INCREASES THE RISK
OF STROKE
AF is associated with a pro-thrombotic state1
~5-fold increase in stroke risk2
AF is the most common heart rhythm disturbance8
Up to 3 million people worldwide suffer strokes related to AF each
year2-4
Due to the aging population, this number is expected to double within
30 years9
AF-related strokes tend to be especially severe and disabling with a
1-year mortality rate of ~50%4,5
Cardioembolic stroke has a 30-day mortality rate of 25%4
Risk of stroke is the same in AF patients regardless of whether they
have paroxysmal or sustained AF6,7
1. Watson T, et al. Lancet 2009;373:155-166. 2. Wolf PA, et al. Stroke 1991;22:983-988.
3. Atlas of Heart Disease and Stroke, World Health Organization, September 2004. Viewed at
http://www.who.int/cardiovascular_diseases/en/cvd_atlas_15_burden_stroke.pdf.
4. Lin HJ, et al. Stroke 1996;27:1760-1764. 5. Marini C, et al. Stroke 2005;36:1115-1119.
6. Rosamond W, et al. Circulation 2008;117:e25-146. 7. Hart RG, et al. J Am Coll Cardiol 2000;35:183-187.
8. Lloyd-Jones DM, et al. Circulation 2004;110:1042-1046. 9. Go AS, et al. JAMA 2001;285:2370-2375.
臺灣中風登錄系
統2006-2008:
30,599 stroke
admissions
Circulation.
2010;122:1
116-1123.)
AF-RELATED STROKES ARE ASSOCIATED WITH
GREATER DISABILITY AND A HIGHER MORTALITY RATE
Strokes without AF (N=845)
Disability at clinical presentation1
30-day post-stroke mortality2
60
30
P<0.005
P<0.0005
50
P<0.048
Fatal strokes (%)
Patients with clinical parameter (%)
Strokes with AF (N=216)
40
30
20
25
20
15
10
10
0
0
Severe limb weakness
Bedridden
Strokes
with AF
Strokes
without AF
(N=103)
(N=398)
1. Dulli DA, et al. Neuroepidemiology 2003;22:118-123. 2. Lin HJ, et al. Stroke 1996;27:1760-1764.
Sources of Cardioembolic Stroke
Others, 10%
Prosthetic Cardiac
Valve, 10%
Nonvalvular AF,
45%
RHD, 10%
Ventricular
Aneurysm, 10%
Acute MI, 15%
AF increases with age
 Prevalence is expected to increase as the population ages
 The lifetime risk of developing AF is 1 in 4 for men and women over 40 years of age
12
Prevalence, %
10
Women
Men
11.1
10.3
9.1
8
7.3
7.2
6
5.0
4
3.0
1.7
2
0.9
0.1 0.2
5.0
3.4
1.7
1.0
0.4
0
<55
55 – 59
60 – 64
65 – 69
70 – 74
75 – 79
80 – 84
>85
Age, years
Source: Go AS, et al. JAMA 2001; 285:2370 – 75; Lloyd-Jones DM, et al. Circulation 2004; 110:1042 – 46
Risk factors for ischaemic stroke/TIA/systemic
embolism in patients with AF
Swedish Cohort Atrial Fibrillation study
Multivariate hazard ratios (95% CI)
Age (years)
<65
65–74
≥75
1.0 (Reference)
2.97 (2.54–3.48)
5.28 (4.57–6.09)
Female sex
1.17 (1.11–1.22)
Previous ischaemic stroke
2.81 (2.68–2.95)
Intracranial bleeding
1.49 (1.33–1.67)
Vascular disease (any)
Myocardial infarction
Previous CABG
Peripheral artery disease
1.14 (1.06–1.23)
1.09 (1.03–1.15)
1.19 (1.06–1.33)
1.22 (1.12–1.32)
Hypertension
1.17 (1.11–1.22)
Heart failure (history)
0.98 (0.93–1.03)
Diabetes mellitus
1.19 (1.13–1.26)
Thyroid disease
Thyrotoxicosis
1.00 (0.92–1.09)
1.03 (0.83–1.28)
Recommendation for screening of AF
Recommendations
• Opportunistic screening for AF in patients
≥65 years of age using pulse-taking
followed by an ECG is recommended to
allow timely detection of AF.
• Class I, level B
Stroke prevention in atrial fibrillation: comparisons
with standard VKA therapy
Meta-analysis of ischaemic stroke or
systemic embolism
VKA vs placebo
VKA vs VKAlow dose
VKA vs ASA
VKA vs ASA + clopidogrel
VKA vs ximelagatran
VKA vs dabigatran
Favours VKA
Adapted after Professor A J Camm, August 30th ESC 2009
Odds/hazard ratio
Favours other Rx
New anticoagulants and their targets in the coagulation cascade
Intrinsic
pathway
Extrinsic
pathway
XII
XI
IX
VIII
Unfractionated
Heparin
Low-MolecularWeight Heparin
VII
X
V
II
I
Fibrin Clot
Adapted from Nutescu EA, et al. Cleve Clin J Med 2005;72 Suppl 1:S2-6
New Xa Inhibitors
• Rivaroxaban
• Apixaban
• Edoxaban
• Betrixaban
• LY517717
• YM150
• Idrabiotaparinux
(Indirect Xa
inhibitor)
Warfarin
New (direct) thrombin
inhibitors
• Dabigatran etexilate
Summary of the clinical trials involving novel anticoagulants
vs. warfarin for stroke prevention in non-valvular AF
Advantages and disadvantages of new anticoagulants vs. warfarin
Advantages and disadvantages of the new oral anticoagulants relative to warfarin
Class
Oral IIa/Xa blockers
Advantages
Disadvantages
No monitoring
Efficacy not yet firmly established
Fast onset of action
Some agents need twice daily dosing
Fast offset of action (in case of bleeding/Short duration of action
surgery)
(thrombosis risk with poor compliance)
Antidote not established
No monitoring, in case of bleeding/
surgery cost
Vitamin-K antagonists
Proven high effictiveness
Monitoring of INR
Therapeutic window established
Drug interaction
Food interaction
Slow onset of action
Antidote established
High bleeding risk
Long action (low thrombosis risk with poor
compliance)
Verheugt F. Neth Heart J 2010; 18(6):314-8
CHAsDS2-VASc
Lip GY et. al. Chest 2010;137:263-72.
Amongst patients with CHADS2
score = 0, the
1-year event rates can range
between 0.84% (CHA2DS2-VASc
score = 0), 1.75% (CHA2DS2VASc score = 1), 2.69%
(CHA2DS2VASc score = 2), and 3.2%
(CHA2DS2-VASc score = 3).
Olesen JB et. al. Thromb Haemost
2012;107:1172–1179.
2012 ESC guidelines for
the choice of anticoagulant
in AF
Antiplatelet therapy with ASA plus
clopidogrel, or-less effectively-ASA
only, should be considered in patients
who refuse any OAC, or cannot
tolerate anticoagulants for reasons
unrelated to bleeding. If there are
contraindications to OAC or
antiplatelet therapy, left atrial
appendage occlusion, closure or
excision may be considered.
Line: solid=best option; dashed=alternative option
NOAC = novel oral anticogulant
Available bleeding risk scores
In AF population
• HEMORR2HAGES
– Hepatic or renal disease, Ethanol abuse, Malignancy,
Older (age ≥75 years), Reduced platelet count or
function, Rebleeding risk, Hypertension (uncontrolled),
Anaemia, Genetic factors, Excessive fall risk, and
Stroke
• HAS-BLED
– Hypertension, Abnormal renal/liver function, Stroke,
Bleeding history or predisposition, Labile INR, Elderly
(e.g. age .65, frailty, etc.), Drugs/alcohol
concomitantly
• ATRIA
– AnTicoagulation and Risk factors In Atrial fibrillation
Management of bleeding in
patients taking novel oral
anticoagulants
• aPTT = activated partial
thromboplastin time;
• NOAC = novel oral
anticoagulant;
• PCC = prothrombin
complex concentrate;
• PT = prothrombin time;
• rFVIIa = activated
recombinant factor VII.
• aWith dabigatran.
Pradaxa (DABIGATRAN ETEXILATE)
•
•
•
•
•
•
Oral prodrug, converted to dabigatran, a potent but reversible DTI
Inhibits both clot-bound and free thrombin
Half-life of 12–17 hours
Peak plasma levels of dabigatran achieved within 2 hours
~80% renal excretion
Most advanced DTI in Phase III development for stroke prevention in
patients with AF (RE-LY® study)
CH3
N
N
N
H3C
O
NH
N
O
O
Dabigatran etexilate
O
H2N
N
O
CH3
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Stangier J, et al. Br J Clin Pharmacol 2007;64:292-303. Sorbera LA, et al. Drugs Future 2005;30:877-885.
Blech S, et al. Drug Metab Dispos 2008;36:386-399.
為什麼有那麼多出血的新聞…paper….警告?
選錯病人
不清楚藥
物正確的
使用方式
嚴重腎功能不全的病人
(肌酸酐清除率小於 30
mL/min)
當病患由warfarin療法
轉用PRADAXA時，須中
斷使用warfarin，並於
INR降至2.0以下時開始
使用PRADAXA
Recommendations for prevention of
thromboembolism in non-valvular AF—bleeding
Recommendations
Class
Level
Assessment of the risk of bleeding is recommended when prescribing
antithrombotic therapy (whether with VKA, NOAC, aspirin/clopidogrel,
or aspirin).
1
A
The HAS-BLED score should be considered as a calculation to
assess bleeding risk, whereby a score ≥3 indicates ‘high risk’ and
some caution and regular review is needed, following the initiation of
antithrombotic therapy, whether with OAC or antiplatelet therapy (LoE
= A).
Correctable risk factors for bleeding [e.g. uncontrolled blood pressure,
labile INRs if the patient was on a VKA, concomitant drugs (aspirin,
NSAIDs, etc.), alcohol, etc.] should be addressed (LoE = B).
Use of the HAS-BLED score should be used to identify modifiable
bleeding risks that need to be addressed, but should not be used on
its own to exclude patients from OAC therapy (LoE = B).
2a
A,B
The risk of major bleeding with antiplatelet therapy (with aspirin–
clopidogrel combination therapy and – especially in the elderly – also
with aspirin monotherapy) should be considered as being similar to
OAC.
2a
B
Recommendations for prevention of
thromboembolism in non-valvular AF—general
Recommendations (1)
Class
Level
Antithrombotic therapy to prevent thromboembolism is
recommended for all patients with AF, except in those
patients (both male and female) who are at low risk (aged <65 years
and lone AF), or with contraindications.
1
A
The choice of antithrombotic therapy should be based upon the
absolute risks of stroke/thromboembolism and
bleeding and the net clinical benefit for a given patient.
1
A
The CHA2DS2-VASc score is recommended as a means of
assessing stroke risk in non-valvular AF.
1
A
In patients with a CHA2DS2-VASc score of 0 (i.e., aged <65 years
with lone AF) who are at low risk, with none of the
risk factors, no antithrombotic therapy is recommended.
1
B
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)d
… is recommended, unless contraindicated.
1
A
Recommendations for prevention of
thromboembolism in non-valvular AF—general
Recommendations (2)
Class
Level
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)d
…. should be considered, based upon an assessment of the risk of
bleeding complications and patient preferences.
2a
A
Female patients who are aged <65 and have lone AF (but still have
a CHA2DS2-VASc score of 1 by virtue of their
gender) are low risk and no antithrombotic therapy should be
considered.
2a
B
When patients refuse the use of any OAC (whether VKAs or
NOACs), antiplatelet therapy should be considered,
using combination therapy with aspirin 75–100 mg plus clopidogrel
75 mg daily (where there is a low risk of bleeding)
or—less effectively—aspirin 75–325 mg daily.
2a
B
Thanks for your
attention! God is
with you!!
•壬林見詩經大
雅 壬，大也，
林，多也。嘏為
福之古字