Download Stroke prevention and risk management for patients with non

Stroke prevention and risk management for
patients with non-valvular atrial fibrillation
Dr Bruce Campbell
Consultant Neurologist, Head of Hyperacute Stroke
Royal Melbourne Hospital
University of Melbourne
Australia
Disclosure: AntiCoagAF app
$1.99 - Proceeds to RMH
Neuroscience Foundation
Key messages – personal viewpoint:
Anticoagulants are grossly underutilised in
Australia (and worldwide)
unnecessary strokes & disability
Act of omission vs act of commission
discrepancy in prescriber thinking regarding
risk-benefit
Age discrimination, lack of creativity and
effort to circumvent relative contraindications
Myths about NOACs versus warfarin
Who needs anticoagulation?
Mechanical heart valves
Deep venous thrombosis/Pulmonary
embolism
Primary/secondary prevention of ischemic
stroke (AF+)
Miscellaneous – antiphospholipid
syndrome, nephrotic syndrome…
Who needs anticoagulation?
How much AF is enough?
Clinically evident/symptomatic episodes are the
tip of the iceberg
Paroxysmal AF has similar stroke risk to
permanent AF
However 30sec of AF on a holter monitor
(minimum definition) may have different risk to
several hours
Spontaneous echo contrast (clot) can develop
over ~20mins
Who needs anticoagulation?
s
t
n
How hard should we look?
ie
t
a
p
e
k -lead ECG
After a stroke or TIA the standardtr12
o
s
n
i
+/- Holter monitor misses paroxysmal
AF!
F
A
y
r
ta
o
s
f
ly tion
l
a
c
i
ta
i
n
l
i
i
l
c hab
r
6 months 8.9%
o
t
e
i
n ng r
o
m u ri
12 months 12.4%
o
t
d
e
u
36 months 30.0%
in
t
n
Co
CRYSTAL-AF Sanna NEJM 2014
Who needs anticoagulation?
2
≥
Risk stratification for atrial fibrillation: CHADS2
S
D
CHADS2 HA
Annual stroke risk
C
y
l
l
a
C – congestive heart failure atic0 ted 1.9%
m i ca
o
t
d1
u
n
a
i
2.8%
H – hypertension
e
n
k
io
o
t
r
t
a
l
A – age >75 ic s agu
2
4.0%
m ico
e
h
t
c
n
D - diabetes
s
a
i
3
5.9%
.
n
e
.
a
i
r
e
t
S2
Af – previous stroke/TIA
4
8.5%
(2 points)
Need to review regularly in those
not yet taking anticoagulant
5
12.5%
6
18.2%
Atrial fibrillation – CHA2DS2-VASc score
Lip et al, Chest 2010
??
Aspirin??
Meta-analysis: 19% reduction in stroke (nonsignificant)
Only SPAF-1 showed a significant reduction in
stroke (by 42%) but heterogeneity between warfarin
eligible and ineligible patients
AVERROES trial – apixaban 5mg BD same risk of
ICH (0.4%pa) and much more effective
(dabigatran rate of ICH similar)
NICE (UK) 2014 recommendations:
“Do not offer aspirin monotherapy solely for stroke
prevention to people with atrial fibrillation.”
Warfarin or NOAC/DOAC?
Figures obtained by the ABC reveal Pradaxa has been
associated with 280 deaths in Australia and 1,400 adverse
drug reactions in the past five years, including abdominal
bleeding, brain haemorrhages, strokes and heart attacks.
By comparison, the older blood-thinning drug Warfarin has
been linked to 30 deaths and 270 reactions over the same
period – Sophie Scott, ABC News Medical Reporter.
Warfarin or NOAC?
Warfarin
Comment
“Tried and tested”
Would warfarin be licensed today?
“Reversible”
Mortality after ICH no different for
warfarin vs NOAC despite “reversal”
“Able to monitor”
NOACS can be monitored but more
specialised testing required
“Can use if poor renal
function”
True but bleeding risk increases
nonetheless
If you are going to use warfarin target INR 2.5 and
do not accept INR <2.0! (not protective)
Warfarin or NOAC?
NOAC
Comment
“No need for monitoring”
Still need to periodically check CrCl
“No major food and drug
interactions”
“Easy adherence”
Less than warfarin but there are some
Perhaps but if miss doses rapidly
unprotected due to shorter half-life
Dabigatran:
increased effect with strong P-gp inhibitors eg ketoconazole
(also amiodarone, verapamil but dose adjustment not recommended),
decreased effect with rifampicin
Xa inhibitors:
increased effect with combined P-gp and CYP3A4 inhibitors - azole-antimycotics
(ketoconazole, itraconazole, voriconazole, posaconazole), HIV protease inhibitors
(e.g. ritonavir, indinavir, lopinavir)
decreased effect with combined P-gp and CYP3A4 inducers - rifampicin, phenytoin,
carbamazepine, phenobarbital or St. John’s Wort
Evidence for novel anticoagulants
Primary/secondary prevention of ischemic stroke in patients with AF:
Dabigatran 150mg BD is superior to warfarin in preventing stroke and
has a reduced risk of intracerebral hemorrhage. Total major bleeding is
higher than warfarin (mostly GI bleeds)
Dabigatran 110mg BD is non-inferior to warfarin in preventing stroke
and has a reduced risk of bleeding, especially intracerebral hemorrhage.
GI bleeding occurred in 1.12%pa vs warfarin 1.02%pa (p=0.43).
Rivaroxaban 20mg daily is non-inferior to warfarin in preventing stroke
and has a reduced risk of intracerebral hemorrhage. Total major
bleeding is similar to warfarin.
Apixaban 5mg BD is superior to warfarin in preventing stroke and has a
reduced risk of intracerebral hemorrhage. Total major bleeding is lower
than warfarin.
Apixaban 5mg BD is superior to aspirin in preventing stroke and has
similar risk of intracerebral hemorrhage and total major bleeding.
Edoxaban 60mg daily is non-inferior to warfarin in preventing stroke
and has a reduced risk of major bleeding & intracerebral hemorrhage.
Risk-Benefit
Consider absolute risk of stroke vs bleeding AND potential consequences of each
Source: NPS
NB no head to head comparison available
Reversibility of warfarin is an illusion
In intracerebral hemorrhage even
prothrombinex is too slow to prevent growth
Mortality is the same for warfarin ICH as
NOAC ICH despite “lack of antidote”
NOACs much less likely to cause ICH in the
first place
Antidotes in phase 3 trials – instant reversal
Reversal and antidotes?
Hart et al Stroke 2012
From RELY
ICH rates:
Warfarin 0.76%pa
150mg 0.31%pa
110mg 0.23%pa
Biggest risk factor
for ICH =
concomitant Aspirin!
Reversal and antidotes
ICH rates with Xa inhibitors
warfarin
Xa
aspirin
p-value
AVERROES
-
0.4%pa
0.4%pa
0.69
ARISTOTLE
0.8%pa
0.33%pa
<0.001
ROCKET-AF
0.7%pa
0.5%pa
0.02
RELY
0.74%pa 150mg BD 0.3%pa 110mg BD 0.23%pa (p<0.001)
Xa antidote and anti-dabigatran Fabfragment antidote now in phase 3 trials
major bleeding
Fatal bleeding
Intra-cranial bleeding
Clinically relevant non-major bleeding
Age discrimination - efficacy vs bleeding
Dabigatran post-hoc data:
Stroke
Warfarin
DBG 110
DBG 150
Age <75
1.43 %/yr
1.32 %/yr
0.90 %/yr
Age ≥ 75
2.14 %/yr
1.89 %/yr
1.43 %/yr
Extracranial Warfarin
bleeding
DBG 110
DBG 150
Age <75
2.44 %/yr
1.76 %/yr
1.91 %/yr
Age ≥ 75
3.44 %/yr
4.10 %/yr
4.68 %/yr
Intracranial Warfarin
bleeding
DBG 110
DBG 150
Age <75
0.14 %/yr
0.26 %/yr
0.61 %/yr
Age ≥ 75
1.00 %/yr
0.37 %/yr
0.41 %/yr
NB ICH lower than warfarin regardless of age
Eikelboom Circulation 2011
Older patients have higher
stroke risk and higher bleeding
risk
Does lower CrCl alter risk-benefit?
Stroke/Systemic Embolism
Major Bleeding
Hohnloser et al Eur Heart J 2012
Does lower CrCl alter risk-benefit?
APIXABAN vs WARFARIN
Stroke or Systemic embolism
Major Bleeding
Hohnloser et al Eur Heart J 2012
Does lower CrCl alter risk-benefit?
DABIGATRAN vs WARFARIN – Stroke or systemic embolism
Connolly NEJM 2009
Major bleeding
Hijazi Circulation 2014
Does lower CrCl alter risk-benefit?
Warfarin
Dabigatran 110mg
Warfarin
Dabigatran 110mg
Warfarin
Dabigatran 150mg
Warfarin
Dabigatran 150mg
Hijazi Circulation 2014
Hijazi Circulation 2014
Does lower CrCl alter risk-benefit?
Rivaroxaban vs warfarin
Stroke or systemic embolism
CrCl (ml/min)
Major bleeding
CrCl (ml/min)
Patel NEJM 2011
When to commence post stroke?
No good evidence
Balancing risk of hemorrhagic transformation
(related to infarct volume) versus recurrent
embolism
Warfarin generally
immediate
for TIA
3-6 days for moderate stroke
10-14 days for major stroke
– probably similar for NOAC despite immediate action
Anticoagulation after ICH??
Any such use is “off-label”
Consider if
high absolute risk of ischemic stroke (eg CHADS ≥4) and
mitigating circumstances eg
Context – trauma, high INR etc
Uncontrolled hypertension (not if amyloid)
Would you use Warfarin vs NOAC vs aspirin?
“reversibility” vs risk of ICH
vs effectiveness in preventing ischemic stroke
When to start antithrombotics after ICH??
Amyloid angiopathy
recurrence risk (not on anticoagulation*)
~5.4%/yr (up to 14%/yr in some studies)
Hypertensive ICH
recurrence risk (not on anticoagulation*)
~2%/yr
Bailey Neurology 2001
Amyloid angiopathy
recurrence risk: antiplatelet effect
prospective cohort 104 lobar ICH patients
Biffi Neurology 2010
Absolute risk of ischemic stroke
un-anticoagulated:
CHADS2
Annual stroke risk
0
1.9%
1
2.8%
2
4%
3
5.9%
4
8.5%
5
12.5%
6
18.2%
CHADS2
C – congestive heart failure
H – hypertension
A – age >75
D - diabetes
S2 – previous stroke/TIA
(2 points)
Starting anticoagulation – my practice
NOACs preferred if CrCl acceptable
NOACs even more dependent on adherence
(short t½)
All 3 agents are reasonable choices
(no head to head data)
If already taking Warfarin and excellent time in
therapeutic range reasonable to continue
– less ICH with NOAC but NNT ~200pa
“warfarin is out… and aspirin is mega-out!”
Hans-Christoph Diener
Use the correct dose:
don’t compromise efficacy
Calculate Renal function = CrCl
(Cockcroft-Gault, not just eGFR!)
Apixaban: 5mg BD unless 2 of age>80, Cr>133μmol/L,
wt<60kg 2.5mg BD
Do not use if CrCl<25ml/min (27% renal clearance)
Dabigatran: 150mg BD unless CrCl 30-50ml/min or
age>75 110mg BD
Do not use if CrCl<30ml/min (80% renal clearance)
Rivaroxaban: 20mg daily unless CrCl 30-50ml/min 15mg daily
Do not use if CrCl<30ml/min (35% renal clearance)
Maximising safety
Control hypertension
Avoid concurrent antiplatelets
Monitor CrCl, especially if intercurrent illness
Take home messages
For NVAF patients new to anticoagulation with
CrCl>25ml/min why would you use warfarin?
For patients “stable” on warfarin consider TTR
and weigh the risk of ICH
“reversibility” of warfarin after ICH is an illusion
Poor renal function with CrCl>25ml/min –
apixaban may be safer than warfarin
Maintain tight BP control and avoid concurrent
antiplatelets
Don’t use aspirin for AF
tPA and NOACs
Known to have taken <12hr = tPA
contraindicated
Otherwise for dabigatran – check dilute
thrombin time (DBG<40ng/mL)
For apixaban <10ng/ml/rivaroxaban
<100ng/ml on calibrated anti-Xa
Or use endovascular therapy (faster…)
Peri-operative management
First ask if necessary to stop
No need to “bridge” with Clexane if NOAC
Time off NOAC:
renal
function
surgical bleeding risk
Peri-operative management
Factor Xa
Low risk = stop 24hr pre and
* 48hr recommended if CrCl 30-49ml/min
restart 24hr post
High risk = stop 48hr pre and
* 72hr recommended if CrCl 30-49ml/min
restart 48hr post
Apixaban:
Ward 2013, Thrombosis J
* Tran IMJ 2014
Peri-operative management
Dabigatran:
CrCl (ml/min) estimated t½ high risk
standard risk
>80
13hr
48hr
24hr
50-80
15hr
48-72hr
24-48hr
30-50
18hr
4 days
48-72hr
Practical Guide to Pradaxa in NVAF, Boehringer Ingelheim