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Stroke prevention in AF - 2015
Dr Ronald M Jardine
Linmed Hospital, Benoni
25 October 2015
AF increases the risk of stroke
o AF is associated with a ~5 fold increase in stroke risk
i.e. to ~5% per year1
o Risk of stroke is the same in AF regardless of whether it is paroxysmal / persistent / permanent 2,3
o AF is associated with 15-20% of all strokes
o Up to 3 million people suffer AF related stroke each year worldwide4
1. Wolf PA et al. Stroke 1991; 22: 983-8. 2. Rosamond W et al. Circulation 2008; 117: e25–146. 3.Hart RG et
al. J Am Coll Cardiol 2000; 35: 183-187. 4. Atlas of Heart disease and Stroke, World Health Organisation,
September 2004. http://www.who.int/cardiovascular_diseases/en/cvd_atlas_15_burden_stroke.pdf
Stroke severity in AF
AF-related strokes tend to be especially
severe and disabling
o 30-day mortality = 25%1
o 1-year mortality = 50%2
1. Lin HJ et al. Stroke severity in atrial fibrillation: the Framingham study. Stroke 1996; 27: 1760-4.
2. Marini C et al. Stroke 2005; 36: 1115-9.
Gladstone DJ et al. Stroke 2009; 40: 235-240.
Effect of first ischaemic stroke in patients with AF (n=597)1
Stroke severity in patients with AF%
of
pa
tie
nts
Disabling Fatal
60%
40%
0%
50%
30%
20%
10%
Economic burden of AF
The American Heart Association estimates that
the direct and indirect cost of stroke in the US is $65.5 billion pa1
A 15% reduction in stroke-related hospital admissions
in the UK would save an estimated
£30 million/year3
A German Registry has shown that the overall
first-year cost of AF is €18,5172
1. Rosamond W et al. Circulation 2008; 117: e25–146. 2. Kolominsky-Rabas PL et al. Stroke 2006;37: 1179–83. 3. Stewart S et al. Heart 2004; 90: 286–292.
Thrombo-embolism in AF
o Thrombus from LA / LAA
Thrombus from LA/LAA
Virchow’s triad
o Stasis
o Endothelial dysfunction
o Hyper-coagulable state
Watson T et al. Lancet 2009; 373: 155-66.
Thrombo-embolism in AF
o Thrombus from LA / LAA (only 75%)
o Other cardio-embolic, e.g. prosthetic valve,
LV aneurysm
o Aortic atheroma
o Cerebro-vascular disease
CHADSVASc score
Risk factor Score
o CHF / LV dysfunction 1
o Hypertension 1
o Age > 75 2
o Diabetes mellitus 1
o Stroke/TIA/other embolism 2
o Vascular disease 1
o Age 65-74 1
o Sex category (female) 1
Max score 9
Stroke rate according to CHADSVASc
Score % per annum
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
ESC recommendations
o CHADSVASc score = 0
Aspirin or nothing
Preferrably nothing
o CHADSVASc score = 1
Consider Oral Anticoagulant (OAC)
Preferrably Novel OAC (NOAC)
o CHADSVASc score = 2 or more
Oral Anticoagulant mandatory
Preferrably Novel OAC
HAS-BLED score
Risk factor Score
o Hypertension 1
o Abn renal/liver function 1-2
o Stroke 1
o Bleeding 1
o Labile INR 1
o Elderly (>65) 1
o Drugs / alcohol 1-2
Max score 9
ESC Guideline 2012.
Coagulation cascade
Vit K
Antagonists
II
VII
IX
X
Anti-thrombotic therapy in AF
Hart RG et al. Ann Intern Med 2007; 146: 857-67.
64
Anti-thrombotic therapy in AF
Hart RG et al. Ann Intern Med 2007; 146: 857-67.
22
Anti-thrombotic therapy in AF
Hart RG et al. Ann Intern Med 2007; 146: 857-67.
38
Brush up on Warfarin - 1
o Anti-coagulate all those who require it
o Educate patients starting warfarin
o Understand the reason for treatment
o Understand what warfarin does
o The meaning of the INR
o Appropriate response to bleeding
o Vitamin K and other antidotes
o Drug-drug (especially non-prescription) and food-drug
interactions
o MedicAlert bracelet
o Frequency of INR monitoring and a log book
Dalby AJ, Wessels P and Opie LH. S Afr Med J 2013; 103: 901-4.
Brush up on Warfarin - 2
o Take steps to ensure patient compliance
o System to ensure regular monitoring of INR
-Lab
-Patient self-monitoring?
o Use an algorithm to guide dose adjustment. Algorithm
consistent dosing relates to better TTR, which in turn
relates strongly to thromboembolic and bleeding outcomes
o Follow an accepted protocol for bridging the peri-operative
period
o Calculate the dose on a weekly, rather than daily basis because
the recommended dose changes are small and will be difficult
to achieve with daily dosing.
o Do weekly INR monitoring for out-of-range INR values.
o (INR 5.00-8.99 + high bleeding risk or when INR >9.00, give
Vitamin K 2.5 mg p.o.)
INR Dose adjustment
<1·50 +15%
1·51-1·99 +10%
2·00-3·00 No change
3·01-4·00 -10%
4·00-4·99 No dose for one day & then -10%
5.00-8.99 No dose until INR therapeutic & then -15%
van Spall HGC, Wallentin L, Yusuf S et al. Circulation 2012; 126: 2309-16.
RE-LY algorithm
Bridging therapy: Cleveland Clinic
Timing Action
Day 5 before surgery if INR 2-3
Day 6 before surgery if INR 3-4.5
Stop warfarin
36 hours after stopping warfarin Start enoxaparin 1 mg/kg 12 hourly
24 hours before surgery Stop enoxaparin
Day of surgery Check INR to ensure <1.2
Day 1 after minor surgery
Day 1 after major surgery/ high bleeding risk
Day 1 after surgery
Resume enoxaparin full dose
Start enoxaparin prophylactic dose
and reintroduce full dose in
consultation with surgeon
Recommence warfarin
Every day after surgery Do INR
When INR >2 for 2 consecutive days Discontinue enoxaparin
Jaffer AK. Cleveland Clinic J Med 2009; 76 (supp 4): S37-S44.
Peri-operative bridging anticoagulation
in patients with atrial fibrillation
BRIDGE trial
In patients with AF who had warfarin treatment
interrupted for an elective operation or other invasive
procedure, forgoing bridging anticoagulation
o was noninferior to peri-operative bridging with
LMWH for the prevention of arterial
thromboembolism and
o decreased the risk of major bleeding.
Douketis JD et al. N Engl J Med 2015; DOI:10.1056/NEJMoa1501035
When is it not necessary
to stop warfarin?
Jaffer AK. Cleveland Clinic J Med 2009; 76(supp 4): S37-S44.
Limitations of VKA therapy
Unpredictable
response
Routine coagulation
monitoring
Slow onset/offset
of actionWarfarin resistance
VKA 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)
1. Ansell J et al. Chest 2008; 133: 160S-198S. 2. Umer Ushman MH et al. J Interv Card Electrophysiol 2008;
22: 129-37. 3. Nutescu EA et al. Cardiol Clin 2008; 26: 169-87.
Narrow therapeutic range with VKA
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 >4.5
0
20
40
60
80
Events
/ 1
000 p
atient
years
Intracranial haemorrhage
Ischaemic stroke
The anticoagulant
effect of vitamin K
antagonists is
optimized when
therapeutic doses are
maintained within a
very narrow range
Hylek EM et al. N Eng J Med 2003; 349: 1019-26.
ACTIVE-W trial: mean TTR by country
Connolly SJ et al. Circulation 2008; 118: 2029-37.
RE-LY: mean TTR by countryM
ean T
TR (
%)
10
30
50
60
70
80
0
Country
20
40
Tai
wan
Mex
ico
Per
u
Ro
man
ia
Ind
ia
Co
lom
bia
Ru
ssia
Bra
zil
Ch
ina
Ko
rea
Gre
ece
Th
aila
nd
Mal
aysi
a
Po
lan
d
So
uth
Afr
ica
Jap
an
Fra
nce
Slo
vak
ia
Po
rtu
gal
Cze
ch R
epu
bli
c
Isra
el
Ph
ilip
pin
es
Bu
lgar
ia
Hu
ngar
y
Ho
ng K
on
g
Tu
rkey
Bel
giu
m
Un
ited
Sta
tes
Au
stri
a
Sp
ain
Ger
man
y
Sw
itze
rlan
d
Sin
gap
ore
Arg
enti
na
Net
her
lan
ds
No
rway
Can
ada
Un
ited
Kin
gd
om
Ital
y
Ukra
ine
Den
mar
k
Au
stra
lia
Fin
lan
d
Sw
eden
4447 48
49 4953 53 54 55 55 56 56 56 57 58 58
60 60 61 6264 64 64 64 64 65 65 66 66 66
67 68 6870 70 70 71 71 72 72 72
74 7477
Wallentin L et al. Lancet 2010; 376: 975–83.
58
1. Kalra L et al. BMJ 2000; 320: 1236-1239 * Pooled data: up to 83% to 71% in individualized trials. 2. Matchar DB et al. Am J Med 2002; 113: 42-51.
66%
44%
9%
18%
38%
25%
<2.0 2.0 – 3.0 >3.0 INR
% o
f e
ligib
le p
atie
nts
rece
ivin
g w
arf
arin
Clinical trial1
Clinical practice2
INR control in clinical trial versus
clinical practice
Coagulation cascade
Direct
thrombin (IIa)
inhibitors
Factor
Xa
inhibitors
Novel Oral Anti-coagulants
o Direct thrombin inhibitor = dabigatran
Pradaxa®
Boehringer-Ingelheim
o Factor Xa inhibitors – rivaroxaban
Xarelto®
Bayer
apixaban edoxaban
Eliquis® Savaysa®
BMS/Pfizer Daiitchi-Sankyo
NOAC in nonvalvular AF -
4 landmark trials
o RE-LY* dabigatran
o ROCKET-AF** rivaroxaban
o ARISTOTLE*** apixaban
o ENGAGE-AF (TIMI 48)**** edoxaban
*Connolly SJ et al. N Engl J Med 2009; 361: 1139-51.
**Patel MR et al. N Engl J Med 2011; 365: 883-91.
***Granger C et al. N Engl J Med 2011; 365: 981-92.
****Giugliano RP et al. N Engl J Med 2013; 369: 2093-104.
NOAC – 4 landmark trials
o RE-LY dabigatran 150mg BD 19 013
dabigatran 110mg BD
o ROCKET-AF rivaroxaban 20mg OD 14 263
o ARISTOTLE apixaban 5mg BD 18 201
o ENGAGE –AF edoxaban 60mg OD 21 105
edoxaban 30mg OD
(All vs dose-adjusted warfarin INR 2-3)
Total 71 683
NOAC trials – Primary end-point
Stroke or systemic embolism
Ruff CT, Giugliano RP, Braunwald E et al. Lancet 2014; 383: 955-62.
Secondary efficacy and safety
outcomes
Ruff CT, Giugliano RP, Braunwald E et al. Lancet 2014; 383: 955-62.
Major bleeding
Ruff CT, Giugliano RP, Braunwald E et al. Lancet 2014; 383: 955-62.
Practical issues with NOACs:
- pharmacological
- co-morbidity
Practical issues - pharmacological
o Patient selection
o Drug selection
o Dose selection
o Adherence errors
o Switching Warfarin to NOAC
o Switching NOAC to Warfarin
o Measuring anti-coagulant effect
o Drug interactions
Patient selection
New AF patients
o All
Existing Warfarin patients
o TTR <60%
o Stroke/embolism on Warfarin
o Bleeding on Warfarin
o Distant laboratory
o Poor venous access
o Patient preference / means 39
Drug selection
Savelieva I and Camm AJ. Clin Cardiol 2014; 37: 32-47.
Metabolism/excretion of NOACs
Heidbuchel H et al. Europace 2013; 15: 625-51.
Drug selection
Savelieva I and Camm AJ. Clin Cardiol 2014; 37: 32-47.
Use full dose as a rule….
But use reduced dose for:
All patients > 80 years old
Patients 75-80 with HAS-BLED score >3
Body weight < 60kg
Moderate renal dysfunction (Cr Cl 30-50ml/min)
GORD (with dabigatran)
Dose selection
o Full dose = dabigatran 150mg BD
rivaroxaban 20mg OD
apixaban 5mg BD
edoxaban 60mg OD
o Reduced dose = dabigatran 110mg BD
rivaroxaban 15mg OD
apixaban 2.5mg BD
edoxaban 30mg OD
Adherence errors
o Missed dose
o Double dose
o Uncertainty
If a patient misses a dose…..
The half-way rule
Time since missed dose Recommendation
<half-way* The patient should take the ‘missed’ dose
>half-way* The patient should wait until their next
scheduled dose
46Huisman M et al. Thromb Haemost 2012; 107: 838-47.
*Half-way = 6 hours for dabigatran and apixaban,
12 hours for rivaroxaban and edoxaban
Adherence errors
o Missed dose half-way rule
o Double dose BD skip next dose
OD take next dose
o Uncertainty BD no stat dose
OD stat dose
Switching patients to NOAC
Stop warfarinAllow INR
to fall below 2.0
Start NOAC
48
Huisman M et al.
Thromb Haemost 2012; 107: 838-47,
Warfarin to NOAC
Parenteral to NOAC
Start NOAC up to 2
hours before next
parenteral drug dose
Start NOAC at
time of
discontinuation of
continuous
infusion
Continuous infusions to NOAC
Switching from Xa inhibitors
o Start warfarin 3 days before stopping Xa
Switching patients from dabigatran
CrCl in mL/min Recommendation
≥50 Start VKA 3 days before stopping NOAC
≥30 to <50 Start VKA 2 days before stopping NOAC
15–30 Start VKA 1 day before stopping NOAC
50Huisman M et al. Thromb Haemost 2012; 107: 838-47.
Dabigatran to parenteral
Start parenteral anticoagulant 12 hours after last dose of NOAC
Start Warfarin based on renal function:
Starting a parenteral anticoagulant:
Close correlation between dabigatran plasma concentration and degree of
anticoagulant effect
Measuring anti-coagulant effect - dabigatran
van Ryn J et al. Thromb Haemost 2010; 103: 1116–27.
4.84.44.03.63.22.82.42.01.61.20.8
0 200 400 600 800 1000Dabigatran plasma concentration (ng/mL)
b12
0
0 200 400 600 800 1000Dabigatran plasma concentration (ng/mL)
a
3.6
0.9
0 200 400 600 800 1000Dabigatran plasma concentration (ng/mL)
d45
40
35
30
25
20
15
10
5
0
0 200 400 600 800 1000Dabigatran plasma concentration (ng/mL)
c
9
6
3
1.2
1.6
2.0
2.4
2.8
3.2
PT
(IN
R)
EC
T (
rati
o)
aPT
T (
rati
o)
TT
(se
c)
Multiple dose
y = 2.4040 + 0.05851x
r2 = 0.8568
Multiple dose
y = 0.86 + 0.06873x1/2
r2 = 0.8514
Multiple dose
y = 1.358 + 0.00962x
r2 = 0.9164
Multiple dose
y = 1.047 + 0.00246x
r2 = 0.8459
INR is not sufficiently sensitive and cannot be recommended
Measuring anti-coagulant effect - dabigatran
o Qualitative tests –
activated Partial Thromboplastin Time (aPTT)
Thrombin Time (TT)
o Quantitative tests–
Ecarin clotting time (ECT)
Hemoclot® thrombin inhibitor assay
52
Measuring anti-coagulant effect - dabigatran
53
1. Van Ryn J et al. Thromb Haemost 2010; 103: 1116–1127.
2. Liesenfeld K-H et al. Br J Clin Pharmacol 2006; 62: 527–537.
3. Huisman M et al. Thromb Haemost 2012; 107: 838-47.
Clinically relevant
measurement
An aPTT >80 seconds at
trough (when the next dose
is due) is associated with a
higher risk of bleeding1,3
Activated partial
thromboplastin time (aPTT)
May be useful in determining
an excess of anticoagulant
activity1,2
Measuring anti-coagulant effect -
Xa inhibitors
o Qualitative
Prothrombin time (PT)
(not INR)
o Quantitative
Anti-Xa chromogenic assay
54
Drug interactions
Drug interactions
o Few
o Verapamil – strongly accentuates dabigatran
and edoxaban
o HIV protease inhibitors – strongly accentuates
rivaroxaban and apixaban
Practical issues – co-morbid
o Chronic kidney disease
o Surgery
o Bleeding
o Coronary artery disease
o Acute stroke
o Cardioversion
o Malignancy
Chronic kidney disease
o CKD is an independent risk factor for stroke in
AF
o CKD is a risk factor for bleeding on OAC
o All NOACs are excreted by kidneys
dabi>edoxa>rivaroxa>apixa
o Monitor renal function
o No NOACs if on haemodialysis (Rx warfarin)
Interruption for surgery
o Bridging is never necessary
o When to stop?
o When to restart?
Interruption for surgery –
when to stop?
o Emergency / elective
o Bleeding risk of the procedure
o Renal function in the case of dabigatran
Classification of bleeding risk
o No bleeding risk
o Low bleeding risk
o High bleeding risk
No bleeding risk
No interruption necessary – operate at trough concentration
Low and high bleeding risk
Interruption for surgery –
when to stop?
o Dabigatran Low risk High risk
CrCl >80 24 48
50-80 48 72
30-50 72 96
<30 not used
o Xa inhibitors
CrCl >30 24 48
15-30 36 48
<15 not used
Interruption for surgery –
when to restart?
o Complete haemostasis 6-8 hours
o Incomplete haemostasis 48-72 hours
Managing bleeding
66
*PCC = prothrombin complex concentrate (Haemosolvex®); rFVIIa = recombinant Factor VIIa (Nova-VII®).
Van Ryn J et al. Thromb Haemost 2010; 103: 1116–27.
Patient with bleeding
Life-threateningModerate/severeMild
• Delay next dose or
discontinue treatment
as appropriate
• Supportive Rx
• Mechanical compression
• Fluid replacement
• Blood transfusion
• Oral charcoal
• Haemodialysis
(dabigatran)
• Consideration PCC or
rFVIIa*
• Charcoal filtration
Antidotes to NOACs?
o Idarucizumab dabigatran:
FAB fragment --- Prax-bind®
o Andexanet alpha Factor Xa inhibitors
Recombinant modified Xa inhibitor
acting as Xa decoy
o Aripazine DTI, Factor Xa inhibitors,
fondaparinux, heparins
Non-specific anticoag reversal by hydrobonding
Idarucizumab
Glund S et al. Presented at AHA 2013.
Fully humanized
antibody fragment (Fab)
Potent binding affinity ~350 times higher than
binding of dabigatran to thrombin
IV administration; immediate onset of action;
short half-life
Well tolerated with a good safety profile, both alone and
in combination with dabigatran
Humanized monoclonal mouse antibody
developed with high dabigatran binding affinity
No procoagulant or anticoagulant effects
Expected low risk of adverse events – no Fc
receptor binding, no endogenous targets
Immediate, complete and sustained reversal of dabigatran
anticoagulation with idarucizumab in healthy volunteers
Glund S et al. Presented at AHA 2013.
Dabigatran plus:
Placebo (n=9)
2 g idarucizumab (day 4) (n=9)
4 g idarucizumab (day 4) (n=8)
Normal upper reference limit (n=86)
Mean baseline (n=86)
Dabigatran + placebo
–2
Time after end of infusion (hours)
dT
T (
s)
Dabigatran Antidote
70
65
60
55
50
45
40
35
30
0 2 4 6 8 10 12 24 36 48 7260
Idarucizumab for dabigatran reversal
o RE-VERSE-AD trial
o Conclusion
Idarucizumab completely reversed the anti-
coagulant effect of dabigatran within minutes.
Pollack CV et al. N Engl J Med 2015; 373: 511-20.
Coronary artery disease
3 different scenarios:
o Patient on OAC for AF develops ACS
o Patient with recent ACS / PCI develops AF
o Patient with stable CAD develops AF
Coronary artery disease
o Patient on OAC for AF develops ACS
Warfarin to be continued DAPT started
NOAC to be stopped DAPT+LMWH
If PCI bare metal stent and
radial artery access if possible
Afterwards: triple for 1 month OAC+SAPT for 1 yr
OAC alone
Coronary artery disease
o Patient with recent ACS/PCI develops AF
Warfarin must be added to DAPT if <1 month
after BMS or <6 months after DES.
If later, consider warfarin alone
warfarin+SAPT
continuing DAPT alone
Xa inhibitor
dabi 110mg BD + SAPT
Coronary artery disease
In deciding, consider….
o Stroke risk i.e. CHADSVASc score
o Bleeding risk i.e. HAS-BLED score
o Athero-thrombotic risk e.g. GRACE score
GRACE* risk score
*Global Registry of Acute Cardiac Events
o Age
o Heart rate
o Systolic BP
o Serum creatinine
o Killip class
o Cardiac arrest at admission
o ST deviation
o Elevated markers
Coronary artery disease
o Patient with stable CAD develops AF
Switch from aspirin to warfarin alone.
NOAC are likely equivalent or better than warfarin.
Dabigatran does increase MI risk slightly
? combine 110mg BD with aspirin.
Acute stroke
o Haemorrhagic – stop OAC immediately
vit K / FFP for warfarin
?PCC / rFVII for NOAC
? Whether to restart after 10-14 days
o Ischaemic – thrombolysis contra-indicated
no interruption for TIA / small infarct
3-6-12 days for small/ medium/large
Cardioversion
o Thrombo-embolic risks with NOACs are the
same as with warfarin
o RE-LY
1983 cardioversions in 1270 patients
30 day stroke risks similar for D110 (0.8%)
D150 (0.3%)
W (0.6%)
Nagarakanti R et al. Circulation 2011; 123: 131-6.
Cardioversion
o X-VERT
1504 patients Xarelto vs Warfarin in 2:1 ratio
Combined end-point 0.51% with X
1.02% with W
Major bleeding 0.61% with X
0.8% with W
Cappato R et al. Eur Heart J 2014.
Malignancy
o Trials excluded cancer patients
o Many cancers increase thrombotic risk
o Cancer therapy increases bleeding risk
o Cardiologist and oncologist joint decision
Physical approaches1
o LAA occlusive devices
Plaato® PLAATO2
Watchman® PROTECT-AF3
Amplatzer cardiac plug®
o Surgical interventions
LAA ligation/purse-string/stapling at other Ø LAAOS
LAA snaring/stapling at thoracoscopy LAPTONI
o Carotid diverters
1. Savelieva I et al. Annals of Medicine 2007; 39: 371-91. 2. Block PC et al. J Am Coll Cardiol Intv 2009;
2: 594-600. 3. Holmes DR et al. Lancet 2009; 374: 534-42.
Percutaneous LAA occlusion
Consider with:
o Ischaemic stroke despite adequate OAC therapy
o Previous intra-cranial haemorrhage
o Recurrent GIT bleeding
o Co-morbidities e.g. uncontrolled HT, cerebral
amyloid angiopathy
o Coagulopathies
Lewalter T et al. Europace 2013; 15: 652-6.
Percutaneous LAA occlusion
Complications:
o Pericardial effusion / tamponade
o Device embolisation
o Stroke
o Myocardial infarction
