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Anticoagulation Symposium & Workshop 2015
Anticoagulation in Atrial Fibrillation
– An Asian Perspective
Dr Yap Lok Bin
Cardiologist
Anticoagulation Symposium & Workshop 2015
Structure
Atrial Fibrillation and OACs among Asians
Warfarin
Our experience of anticoagulants
Risk Scoring
Anticoagulation Symposium & Workshop 2015
Strategies for the management of AF
• Risk stratify: CHA2DS2VAS c or CHADS2 scores
• Anticoagulants (Warfarin or NOACs)
• Underutilized
Stroke prevention
• Adequate rate control defined as achievement of arbitrary heart rate target at rest and exercise
Ratecontrol
• Revert to Sinus Rhythm
• DCCV or Catheter Ablation
• Efficacy defined as “freedom from AF”
Rhythm control
Anticoagulation Symposium & Workshop 2015
Stroke
Stroke is 5 times more likely in patients with atrial fibrillation compared with those without.
A CVA during atrial fibrillation is twice as likely to cause death and disability compared with non embolic strokes
33% of acute strokes in elderly population are related to AF
Anticoagulation Symposium & Workshop 2015Zhang L Stroke 2003
72.562.5
50
14.527.5
34
4.3 1.82.7
8.7 8.2 12.3
0%
20%
40%
60%
80%
100%
Thrift AG
Stroke 2001
North East
Melbourne
Zhang LF
Stroke 2003
China
Huang CY
Stroke 1990
Hong Kong
Ischemic
stroke
Intracerebral
hemorrhage
Undetermined
SAH
High Baseline ICH Risk in Asian
Hospital-based study
10 regions in China (Beijing, Shanghai, Guangzhou)
8,268 stroke patients
Anticoagulation Symposium & Workshop 2015
Ethnic Difference: Risk of Intracranial Hemorrhage with Warfarin for AF
Shen AY, et al. JACC 2007;50:309-15, n = 18,000 Rate of ICH is 20% in whites and 30% in Asians
Asian vs. White: ~4X risk of ICH with warfarin
Anticoagulation Symposium & Workshop 2015
WARFARIN
Anticoagulation Symposium & Workshop 2015
Atrial Fibrillation and Anticoagulation
Prevalence: 5% of people over age 65
10% of people over age 80
Incidence of stroke with afib increases with age:
1.3 %/year in patients 50–59
2.2 %/year in 60–69
4.2 %/year in 70–79
5.1 %/year in 80–89
Anticoagulation Symposium & Workshop 2015
Adjusted dose warfarin and antiplatelet agents have been shown to reduce the risk of stroke compared with control by 64% and 22%
Warfarin has been shown to be more effective than aspirin, in reducing stroke by 45%, but increasing the risk of bleeding
Warfarin and other oral anticoagulants (OAC) are recommended for patients at increased risk of stroke; and aspirin is recommended for patients at lower risk
Warfarin Antiplatelets
• Ann Intern Med 2007; 146: 857-67.
Warfarin vs Aspirin
-64
-22
-70-60-50-40-30-20-10
0
Risk Reduction in Stroke
(%) %
%
Anticoagulation Symposium & Workshop 2015
Warfarin Use
Older patients less likely to receive anticoagulation
Older patients more likely to be
“underanticoagulated” -- even though data is clear
that there is no significant stroke protection at an INR of
less than 2.
Overestimation of “Falls Risk”
Anticoagulation Symposium & Workshop 2015
1930s
Heparin
1950s 1990s 20021970s
Warfarin LMWHs Factor Xa inhibitor
DTIs
ArgatrobanBivalirudinLepirudinIprivask
FondaparinuxEnoxaparinDalteparinTinzaparin
1980s
2010-12
DTI and Factor Xainhibitors
DabigatranRivaroxaban
Apixaban
Developmental History –Current FDA Approved
Anticoagulants
Anticoagulation Symposium & Workshop 2015
Unpredictable response
Routine coagulation monitoring
Slow onset/offset of action
Risk of BleedingComplications
Warfarin therapy has
several limitations
that make it difficult to
use in practice
Numerous drug-drug interactions
Numerous food-drug interactions
Frequent dose adjustments
Narrow therapeutic window (INR range 2-3)
Stroke Prevention in Atrial Fibrillation-Limitations of Warfarin Therapy in Atrial Fibrillation
• Warfarin was #1 in 2003 and 2004 in the number of mentions of “deaths for drugs causing adverse effects in therapeutic use”
• Warfarin caused 6% of the 702,000 ADEs treated in the ED/year; 17% required hospitalization
• J Thromb Thrombolysis 2008; 25: 52-60.
Anticoagulation Symposium & Workshop 2015International Normalised Ratio (INR)
Target INR
(2.0-3.0)
<1.5 1.5–1.9 2.0–2.5 2.6–3.0 3.1–3.5 3.6-4.0 4.1-4.5 >4.50
20
40
60
80
Even
ts /
1000
pat
ient
yea
rs
Intracranial haemorrhageIschaemic stroke
The anticoagulant effect of vitamin K antagonists are optimized when therapeutic doses are maintained within a very narrow range
• N Engl J Med 2003; 349: 1019-26.
Stroke Prevention in Atrial Fibrillation-Limitations of Warfarin Therapy in Atrial Fibrillation-Narrow Therapeutic Window
Anticoagulation Symposium & Workshop 2015
NOACs
Anticoagulation Symposium & Workshop 2015
Advantages NOAC over Warfarin
No monitoring of PT/INR
Less incidence of intracranial haemorrhage
Lower rates of stroke and systemic embolism
Disadvantages of NOAC
High Cost
GI side effects
No antidote available (yet)
Contraindicated in severe renal impairment
Anticoagulation Symposium & Workshop 2015
Anticoagulation Symposium & Workshop 2015
SPAF trials
Re-LY ROCKET-AF
ARISTOTLE
ENGAGE AF-TIMI 48
Drug Dabigatran Rivaroxaban Apixaban Edoxaban
Dose (mg)Freq
150, 110BID
20 (15*)QD
5 (2.5*)BID
60*, 30*QD
N 18,113 14,266 18,206 >21,000
Design PROBE 2x blind 2x blind 2x blind
AF criteria AF x 1< 6 mths
AF x 2(>1 in <30d)
AF or AFl x 2<12 mths
AF x 1 < 12 mths
% VKA naive 50% 38% 43% 40% goal
*Dose adjusted in patients with ↓drug clearance. **Max of 10% with CHADS-2 score = 2 and no stroke/TIA/SEEPROBE = prospective, randomized, open-label, blinded end point evaluation VKA = Vitamin K antagonist
Anticoagulation Symposium & Workshop 2015
There is less haemorrhagic stroke for NOACs
Efficacy outcomes (Asia vs. non-Asia)
RE-LY® Asia
Stroke or SEEAsiaNon-AsiaIschemic strokeAsiaNon-AsiaHemorrhagic strokeAsiaNon-AsiaMyocardial infarctionAsiaNon-AsiaDeath from any causeAsiaNon-Asia
Dabigatran 150mg bidvs. Warfarin
Dabigatran 110mg bidvs. Warfarin
Rate (%/year)
110mg bid
WarfarinDabigatran
1.0 2.00
HR (95%CI)
1.391.06
1.120.81
0.170.09
0.500.86
4.013.57
3.061.48
2.020.98
0.750.32
0.580.65
5.093.96
Interactionp value
Interactionp value
0.0853
0.1977
0.7590
0.3782
0.4244
150mg bid
2.501.37
2.051.14
0.110.12
0.510.88
5.013.53
0.5597
0.5959
0.2729
0.3761
0.5929
1.0 2.00
Dabigatran better Warfarin better
HR (95%CI)
Masatsugu Hori et al. Stroke. 2013;44:1891-1896n = 15,000 non Asians and n = 2700 in Asians
Anticoagulation Symposium & Workshop 2015
Summary of NOACs
Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban
Mode of
Action
Vitamin K
antagonist
Direct
thrombin
inhibitor
Factor Xa
inhibitor
Factor Xa
inhibitor
Factor Xa
inhibitor
Half-life 40 h 14 h 5-9 h 8-13 h 5-13 h
Dose Once daily 110 mg twice
daily
150mg twice
daily
15 mg once
daily
20mg once
daily
2.5 mg twice
daily
5 mg twice
daily
30mg once
daily
60mg once
daily
Stroke
Prevention
(vs warfarin)
- Non-inferior
(110mg)
Superior
(150mg)
Non-inferior
(20mg)
Superior
(5mg)
Non-inferior
(30mg)
Non-inferior
(60mg)
Anticoagulation Symposium & Workshop 2015
Our Experience of NOAC vs Warfarin
Anticoagulation Symposium & Workshop 2015
IJN Study
Anticoagulation Symposium & Workshop 2015
IJN Study
Anticoagulation Symposium & Workshop 2015
What is our Experience of NOAC
compared to Warfarin?
Study of 1000 Clinical records
500 patients prescribed dabigatran vs 500 patients prescribed warfarin at IJN from January 2009 to December 2013.
Examined for stroke rates, adverse effects, bleeding risks with NOACs compared to warfarin
Anticoagulation Symposium & Workshop 2015
500 IJN Patients on Warfarin –
Time in Therapeutic Range
Mean TTR for warfarin is 50%
Median TTR 53%
Anticoagulation Symposium & Workshop 2015
TTR subgroup analysis:
mean TTR by country
25
TTR = time in therapeutic range
Wallentin L et al. Lancet 2010;376:975–83
Mean T
TR (
%)
10
30
50
60
70
80
0
Country
20
40
Taiw
an
Mexic
o
Peru
Rom
ania
India
Colo
mbia
Russ
ia
Bra
zil
Chin
a
Kore
a
Gre
ece
Thaila
nd
Mala
ysi
a
Pola
nd
South
Afr
ica
Japan
Fra
nce
Slo
vakia
Port
ugal
Cze
ch R
epublic
Isra
el
Phili
ppin
es
Bulg
aria
Hungary
Hong K
ong
Turk
ey
Belg
ium
United S
tate
s
Aust
ria
Spain
Germ
any
Sw
itze
rland
Sin
gapore
Arg
entina
Neth
erlands
Norw
ay
Canada
United K
ingdom
Italy
Ukra
ine
Denm
ark
Aust
ralia
Fin
land
Sw
eden
4447 48 49 49
53 53 54 55 55 56 56 56 57 58 5860 60 61 62 64 64 64 64 64 65 65 66 66 66 67 68 68 70 70 70 71 71 72 72 72
74 7477Malaysia
Anticoagulation Symposium & Workshop 2015
Adverse Effects Analysis
Dabigatran Warfarin P value
Dyspepsia 20 (3.9%) 2 (0.4%) <0.01
Shortness of
Breath
6 (1.2%) 0 0.01
Leg oedema 5 (1%) 0 0.03
Palpitations 3 (0.6%) 0 0.13
Dizziness 3 (0.6%) 0 0.13
Chest pain 2 (0.4%) 0 0.16
headache 2 (0.4%) 0 0.16
Allergy 2 (0.4%) 2 (0.4%) 0.50
Flushing 0 2 (0.4%) 0.16
Anticoagulation Symposium & Workshop 2015
Bleeding Risk Analysis
Dabigatran Warfarin P value
Minor Bleeding
Haematuria 5 (1%) 3 (0.6%) 0.23
Gum bleeding 5 (1%) 1 (0.2%) 0.11
Gastrointestinal
bleed
0 3 (0.6%) 0.50
Subconjunctival
haemorrhage
2 (0.4%) 2 (0.4%) 0.69
Retinal haemorrhage 1 (0.2%) 0 0.75
Epistaxis 1 (0.2%) 0 0.75
Major Bleeding
Gastrointestinal
bleed
2 (0.4%) 2 (0.4%) 0.69
Haematuria 1 (0.2%) 0 0.75
Anticoagulation Symposium & Workshop 2015
Clinical Outcome
Follow-up Period
CVA Events Warfarin Dabigatran P value
CVA ischemic 4 (0.8%) 0 0.30
CVA
haemorrhagic
1 (0.2%) 1 (0.2%) 0.92
Warfarin Dabigatran
Average follow up 355 days (11.7
months)
Average follow up 315 days (10.4
months)
Anticoagulation Symposium & Workshop 2015
Reasons for Stopping Warfarin in our Study
Reasons for stopping warfarinSwitched to Dabigatran 42
Bleeding due to warfarin 10
Patient preference 7
INR subtherapeutic / not in range 6
Poor INR control 5
Doctors preference / recommendation 4
Post watchman device on dual anti-platelets 3
Deaths 3
Hot sensation 2
CVA 2
Poor compliance to warfarin 2
Allergy 2
Gastric upset and pain 2
Vomiting 1
Anxiety 1
Difficulty getting to INR clinic 1
Convenience (blood taking ) 1
Anticoagulation Symposium & Workshop 2015
Malaysian registry study supports the
positive efficacy and safety profile of
NOACs in Asia
Yap LB et al. J Thromb Thrombolysis. 2014;38:39–4430
• Observational cohort study
• National Health Institute in Malaysia
• 510 dabigatran users
– 31% switched from warfarin
– 60% taking 150 mg BID dose
– 315 days of follow-up (average)
“The rate of occurrences of adverse effects and bleeding
were lower than those seen in the RE-LY® trial”
OBSERVATION
• 1 haemorrhagic stroke
• 0 ischaemic strokes
• 2 major bleeding (GI)
• Dyspepsia 4%
• Withdrawal 18%
Anticoagulation Symposium & Workshop 2015
Current Guidelines
Anticoagulation Symposium & Workshop 2015
*Or moderate-to-severe left ventricular systolic dysfunction (left ventricular ejection fraction ≤40%)
TIA, transient ischaemic attack; SE, systemic embolism
Olesen et al. BMJ 2011
Increased risk of thromboembolism when CHA2D2s-VASc score ≥2
Add points
together
32
RISK FACTORS SCORE
Congestive heart failure 1
Hypertension 1
Age ≥ 75 2
Age 65-74 1
Diabetes mellitus 1
Stroke/TIA/thrombo-
embolism2
Vascular disease 1
Sex Female 1
Your score
CHA2DS2VASc
SCORE
ADJUSTED
STROKE RATE (%
year)
0 0%
1 1.3%
2 2.2%
3 3.2%
4 4.0%
5 6.7%
6 9.8%
7 9.6%
8 6.7%
9 15.2%
Anticoagulation Symposium & Workshop 2015
HAS-BLED Score
CLINICAL
CHARACTERISTIC
POINTS
AWARDED
Hypertension 1
Abnormal liver function 1
Abnormal renal function 1
Stroke 1
Tendency to bleed 1
Labile INRs 1
Elderly (Age >65) 1
Drugs 1
Alcohol 1
Your score
HAS
BLED
SCORE
NUMBER
OF
PATIENTS
No OF
BLEEDS
BLEEDS
PER
100
PATIENT
YEARS
0 798 9 1,13
1 1286 13 1,02
2 744 14 1,88
3 187 7 3,74
4 46 4 8,70
5 8 1 12,50
6 2 0 0
7 --- --- ---
8 --- --- ---
9 --- --- ---
Total 798 9 1,13
Anticoagulation Symposium & Workshop 2015
2012 ESC guidelines for the choice of anticoagulant in AFAntiplatelet 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
Anticoagulation Symposium & Workshop 2015
CPG on Ischaemic Stroke 2012
Anticoagulation Symposium & Workshop 2015
• Older Asian Patients have higher risks of stroke
• Anticoagulation recommended for those with CHADSVASC score ≥ 2
• Our experience shows that NOACs are effective and safe when compared to warfarin
Summary
Anticoagulation Symposium & Workshop 2015
Additional Slides
Anticoagulation Symposium & Workshop 2015
Case 1 Mr Sidek A 67-year-old man presents to the clinic.
Past history : hypertension, hyperlipidemia,
Type 2 diabetes mellitus.
Current Medication: Bisoprolol 5mg daily, lisinopril 5 mg daily, metformin 500mg XR od, atorvastatin 20 mg daily, aspirin 150 mg daily
Social History: Mobile, independent, smokes 10/day, no alcohol. Works as a food vendor.
BP 120/80 mmHg, irregular pulse HR 70 bpm, eGFR > 60
ECG shows atrial fibrillation
CHADS2 score = 2
CHA2DS2-VASC score = 3
What drug should be given for stroke prevention?
Anticoagulation Symposium & Workshop 2015
Case 2
Mr Wong A 68-year-old man presents to the
clinic with breathlessness.
Past history : hypertension, PCI to LAD in 2008,
CCF, CVA 2012.
Current Medication: bisoprolol 2.5mg daily, Perindopril 4 mg daily, rosuvastatin 20 mg daily, spironolactone 12.5mg bd, aspirin 150 mg daily
Social History: Unemployed and unable to pay for medication.
ECG shows new atrial fibrillation. Rate 80 bpm. eGFR > 60
CHADS2 score = 4
CHA2DS2-VASC score = 7
What drug should be given for stroke prevention?
Anticoagulation Symposium & Workshop 2015
Case 3 Mr Jamal A 70-year-old man presents to the clinic
with palpitations
Past history : Hypertension, PCI to RCA 2013, GI bleed 2012 –OGD showed duodenal ulcer.
Current Medication: Aspirin 100mg od, Plavix 75 mg od, Omeprazole 20mg od, Atenolol 25mg od, Simvastatin 20mg od, Ramipril 5 mg od
Social History: Smoker 20/day, Alcohol 4x a week. Retired Health Professional.
ECG and monitoring showed paroxysmal AF
CHADS2 score = 1
CHA2DS2-VASC score = 3
HAS-BLED score = 4
What drug should be given for stroke prevention?
Anticoagulation Symposium & Workshop 2015