Prevention of recurrent stroke in atrial fibrillation. Comaprison of NOAC vs VKA. Riks of hemorrhagic stroke. When anticoagulation should be initiated following acute stroke.

1. Prevention of recurrent stroke in patient
with atrial fibrillation and high risk of
cerebral bleeding.
Jacek Staszewski MD, PhD
ACUTE STROKE EXPERT WORKSHOP
Almaty, KAZAKHSTAN

2. Disclosures
• Honoraria from Boehringer Ingelheim, Polfarma

3. Choice of antithrombotic therapy in AF
• definite need of anticoagulation regardless of AF type
Caridioembolic risk?
Hemorrhagic risk* ?
*HAS-BLED is not inteded to exclude patients from AC but rather to check modifieble risk factors which could be eliminated

4. Age and risk of intracranial bleeding in the elderly
BAFTA study
Mant J, et al. Lancet 2007;370:493-503.
%majorbleeding(%/ys)
VKA ASA 75 mg/d
4
3
0
2
Patients with AF
≥75 ys
(n=973)
p=0,9
52% stroke risk reduction in VKA group vs ASA
1
ASA:
no significant benefit,
no significant difference
in rate of ICH or major
bleeding,
potential for harm
vs VKA

5. Ansell J et al. Chest 2008;133;160S–98S; Umer Usman MH et al. J Interv Card Electrophysiol 2008;22:129–137;
Nutescu EA et al. Cardiol Clin 2008;26:169–87; www.fda.gov/Drugs/DrugSafety/ucm396470.htm
Limitations restrict the use of VKAs for stroke prevention
Unpredictable
response
Need for routine
coagulation
monitoring
Slow onset/offset
of action
Warfarin annual
ICH rate
close to 1% in
trials, may be
higher in clinical
practice
ICH:  25% major
bleeding
• 2/3 in INR 2-3
• 80% mortality
Numerous food–
drug, drug-drug
interactions
Frequent dose
adjustments
Narrow therapeutic
window
(INR range 2–3)

6. Acronym Definitions Points
S Sex (Female) 1
A Age (<60 years) 1
Me Medical history 1
2 of: HT, DM, CAD, MI, PAD, stroke, pulmonary/hepatic/renal disease
T Treatment interactions 1
T Tobacco use 2
R Race (non-Caucasian) 2
HT = hypertension, DM = diabetes, CAD = coronary artery disease
MI = myocardial infarction, PAD = peripheral artery disease
Factors affecting quality of VKA anticoagulation control
SAMe-TT2R2 score
Apostolakis S i wsp. The SAMe-TT2R2 score. Chest 2013; 144: 1555-1563
0–1 points — patients adequate for VKA
≥ 2 points — patients not adequate for VKA

7. 2012 ESC guidelines recommend NOACs over VKAs
European Society of Cardiology Guidelines. European Heart Journal (2012) 33, 2719–2747
NOACs = novel non vitamin K anticoagulants
Class Level of evidence

8. Novel oral anticoagulants vs warfarin
0,5 1 2
Dabigatran 150 mg 2 x dz.
Dabigatran 110 mg 2 x dz.
Rivaroxaban 20 mg* 1 x dz.
Apixaban 5 mg† 2 x dz.
*15 mg for patients with CrCl 30 – 49 mL/min † 2,5 mg for patients with one of the following: age ≥80 yr, weight ≤60 kg, stęż. creatinine ≥ 1,5 mg /dL.
Connolly SJ, Ezekowitz MD, et al. N Engl J Med. 2009;361:1139-1151; Patel MR, et al. N Engl J Med. 2011;365:883-891; Granger CB, et al. N Engl J Med. 2011;365:981-992.
WFN better
HR (95% CI) p
0,65 (0,52-0,81) <0,001
0,90 (0,74-1,1) 0,29
0,88 (0,75-1,03) 0,12
0,79 (0,66-0,95) 0,01
NOAc better
Indirect comparison: stroke and systemic embolism
Comparison between NOACs is not valid because of population differences among the studies.
No head-to-head data are available.

9. Connolly S et al. NEJM 2009. Patel M et al. NEJM 2011. Granger C et al. NEJM 2011. Wallentin L. ESC 2011.
WFN betterNOAc better
Novel oral anticoagulants vs warfarin
RRR = 25%
p = 0,03
Indirect comparison: Ischemic stroke and unknown origin
Comparison between NOACs is not valid because of population differences among the studies.
No head-to-head data are available.

10. Real-world evidence from >200000 patients is largely
consistent with the results from RE-LY®
10
Risk of occurence
Pradaxa® vs warfarin FDA Medicare
study1
(134 000 patients)
Two large US
health insurances2
(>38 000 patients)
US Department
of Defense3
(>25 000 patients)
Danish
observational
studies4,5*
(>20 000 patients)
Stroke Lower
(ischemic)
Similar Lower n/a
Intracranial
bleeding
Lower Lower Lower Lower
Major bleeding Similar Lower Similar Lower
Major GI bleeding Higher Similar Similar Similar
MI Similar Similar Lower Similar
Mortality Lower n/a Lower n/a
1. Graham DJ et al. Circulation 2014; doi: 10.1161/CIRCULATIONAHA.114.012061; 2. Seeger JD et al. Presented at AHA 2014;
3. Villines TC et al. Presented at AHA 2014; 4. Larsen TB et al. Am J Med 2014;127:650–6.e5; 5. Larsen TB et al. Am J Med 2014;127:329–36.e4
*VKA-naïve stratum, 150 mg BID

11. Please refer to local label: thrombolysis permitted if INR ≤1.3 in the EU
sICH, symptomatic intracranial haemorrhage
Adams HP et al. Stroke 2007;38:1655–711; Xian Y et al. JAMA 2012;307:2600–8
AHA recommendations suggest rt-PA should only be used
in patients receiving a VKA if INR ≤1.7
This concept may be plausible, and seem feasible for daily practice
However, there is no strong evidence for the concept or threshold
Risk of symptomatic ICH
95% CI
Stroke patients receiving rtPA; Graph follows 1802 patients who were receiving warfarin
EU label-recommended
threshold
AHA-recommended
threshold
PL – label: „no effective anticoagulation”
National recommendations: „INR ≤1.7”
VKA+ VKA- OR* p
sICH (%) 5.7 4.6 1.01 .94
Inhospital 11.4 7.9 0.94 .50
mortality

12. Lancet 2001
Cohrane Database 2001
ASA in the treatment of acute phase of ischemic stroke
Recommended regardless of IS etiology
• International Stroke Trial Collaborative Group: The International Stroke
Trial (IST): a randomised trial of aspirin, subcutaneous heparin,
both or neither among 19 435 patients with acute stroke.
Lancet 1997
• CAST – Collaborative Group: CAST-randomised placebo controlled trial
of early aspirin use in 20 000 patients with acute ischemic stroke.
Lancet 1997
Zalecenia ESO, Cerebrovasc Dis 2008
Urgent anticoagulation vs ASA
9 less ischemic strokes
9 more ICH / 1000 treated pts
= NO NET BENEFIT =
Urgent anticoagulation is not recommended for treatment of patients
with acute ischemic stroke (Class III; Level of Evidence A).
Oral administration of ASA (initial dose is 325 mg) within 24 to 48 hrs
after stroke onset is recommended (I, A).
ASA (dosage: 160-325 mg) is recommended in the first 48 hrs
following ischemic stroke (I, A)
ESO Guidelines; Cerebrovasc Dis 2008
AHA/ASA, Guidelines Stroke 2013

13. Choice of antithrombotic therapy after IS
Secondary stroke prevention
Cardioembolic risk ?
Hemorrhagic risk ?

14. This study was not designed to compare NOACs against one another.
D110, dabigatran 110 mg BID; D150, dabigatran 150 mg BID
Ntaios G et al. Stroke 2012;43:3298–304;
NOACs are associated with improved outcomes in patients
with prior stroke/TIA vs warfarin
Peto odds ratio
Peto, fixed, 95% CI
Stroke/SE Haemorrhagic stroke
ARISTOTLE 0.76 (0.56–1.03) 0.42 (0.23–0.77)
RE-LY® D110 0.84 (0.58–1.21) 0.20 (0.08–0.48)
RE-LY® D150 0.75 (0.52–1.09) 0.31 (0.14–0.70)
ROCKET AF 0.94 (0.77–1.17) 0.73 (0.42–1.25)
Total 0.85 (0.74–0.99) 0.44 (0.32–0.62)
Favours NOAC Favours warfarin Favours NOAC Favours warfarin
RE-LY® and ARISTOTLE showed a trend towards benefits of NOACs for
stroke/SE, and significant benefits in haemorrhagic stroke vs warfarin

15. This study was not designed to compare NOACs against one another.
D110, dabigatran 110 mg BID; D150, dabigatran 150 mg BID
Ntaios G et al. Stroke 2012;43:3298–304; Patel MR et al. N Engl J Med 2011;365:883–91
NOACs are associated with improved outcomes in patients
with prior stroke/TIA vs warfarin
Peto odds ratio
Peto, fixed, 95% CI
Stroke/SE Haemorrhagic stroke
ARISTOTLE 0.76 (0.56–1.03) 0.42 (0.23–0.77)
RE-LY® D110 0.84 (0.58–1.21) 0.20 (0.08–0.48)
RE-LY® D150 0.75 (0.52–1.09) 0.31 (0.14–0.70)
ROCKET AF 0.94 (0.77–1.17) 0.73 (0.42–1.25)
Total 0.85 (0.74–0.99) 0.44 (0.32–0.62)
Favours NOAC Favours warfarin Favours NOAC Favours warfarin
No additional benefit for IS and ICH reduction was demonstrated for
rivaroxabanvsVKA, despite ROCKET AF was the best-powered trial to identify
differences vs VKA for secondary stroke prevention (55%oftheincludedpopulation)

16. CoR, class of recommendation; LoE, level of evidence
1. Kernan WN et al. Stroke 2014;45:2160–236; 2. Camm AJ et al. Eur Heart J 2012;33:2719–47
Guidelines support reinitiation of NOAC therapy after an
ischaemic stroke
Higher strength of recommendation for VKA therapy, apixaban,
and dabigatran than for rivaroxaban1
AHA/ASA 2014 guideline recommendations1 CoR LoE
The following are indicated for the prevention of recurrent stroke in patients with NVAF,
whether paroxysmal or permanent:
• VKA therapy I A
• Apixaban I A
• Dabigatran I B
Rivaroxaban is reasonable for the prevention of recurrent stroke in
patients with NVAF
IIa B
ESC 2012 focused update suggests considering dabigatran
150 mg BID in patients on rivaroxaban or apixaban who
experience an ischaemic stroke2

17. Huisman M et al. Thromb Haemost 2012;107:838–47
Re-initiation of anticoagulation depends on severity of
stroke
Stroke severity Restart
TIA
As soon as imaging has excluded a
cerebral haemorrhage
Mild stroke 3–5 days after symptom onset
Moderate stroke* 5–7 days after stroke onset
Severe stroke* 2 weeks after stroke onset
*Repeat imaging is required to exclude haemorrhagic transformation
Time to re-initiation depends on infarct size:
1 – 3 – 6 – 12 day rule (Diener’s Law)
Remember of BP control

18. Case history:
• Dabigatran 2x150 mg/d was initiated on the 7 day after
stroke onset:
• CHADS-VASc: 7 p, HAS-BLED: 2 p
• age: 79 ys; no significant drug-drug interactions (fe. verapamil)
• creatinine clearance ≥ 50 ml/min
• body weight 72 kg
ESC 2012: Recommendation Class Level
When dabigatran is prescribed, a dose of 150 mg BID should be
considered for most patients in preference to 110 mg BID, with the
latter dose recommended in:
• elderly patients, age ≥80 years
• concomitant use of interacting drugs (e.g. verapamil)
• high bleeding risk (HAS-BLED score ≥3)
• moderate renal impairment (CrCl 30–49 mL/min)
IIa B
BID = twice daily; CrCl = creatinine clearance; ESC = European Society of Cardiology; NOAC = novel oral anticoagulant;
Camm AJ et al. Eur Heart J doi:10.1093/eurheartj/eh253

19. Case history:
• Discharged home
• N.exam.: slight neurological
deficit; NIHSS 2p
• Recommendations:
• Regular drug intake
• Control of creatinine clearance and BP

20. Green = quantitative; orange = qualitative only; red = not available
Adapted from references 1–4; 1. Heidbuchel H et al. Europace 2013;15:625–51; 2. Pradaxa®: EU SPC, 2014;
3. Eliquis: EU SPC, 2014; 4. Xarelto: EU SPC, 2014
Consider differences between NOACs when assessing
coagulation status
Dabigatran Rivaroxaban Apixaban
aPTT
TT, dTT [Hemoclot]
ECT
Anti-FXa assays
PT
INR
No t useful
 











 



21. x
• dTT (Hemoclot): not available
• aPTT 8 h after intake: 58 s
• creatinine clearance: 61 ml/min
• PLT: 150, 000 / mL
How to interpret aPTT ?
Consider time of last dabigatran intake and renal function
Exposure to dabigatran is increased by renal impairment and correlates with the
severity of renal dysfunction

22. NOAC vs Warfarin
Safety profile: significant decrease of ICH risk vs VKA
0.5 1
Dabigatran 150 mg BID*
Dabigatran 110 mg BID*
Rivaroxaban 20 mg QD
Apixaban 5 mg BID
Connolly SJ et al. N Engl J Med. 2009;361:1139-1151
Patel MR et al. N Engl J Med. 2011;365:883-891
Chai-Adisaksopha C et al. Blood 2014;124:2450-2458
HR p
0.26 <0.001
0.31 <0.001
0.58 0.012
0.51 <0.001
WFN better
ICH 0.53% vs 1.24% OR 0.49 (0.39–0.56)
Intracerebral hemorrhage OR 0.42 (0.18-1)
Subdural hemorrhage OR 0.54 (0.34-0.81)
NNT 34
NNT 29
NNT 59
NNT 35
NOAC better
* Highest risk reduction among all NOAcs vs warfarin
Indirect comparisons

23. Subdural hemorrhages in RE-LY study
Hart RG et al. Stroke 2012; 43: 1511-1517
Intracranial Hemorrhages in RE-LY
n = 154
Intracerebral
46%
Subdurachnoid
8%
Subdural
45%
Spontaneous: 56%

24. Subdural hemorrhages in RE-LY study
Hart RG et al. Stroke. 2012; 43: 1511-1517
Subdural
hemorrhage
Mortality rates*
Warfarin
% (n/n)
Dabigatran 150 2 x 1
% (n/n)
Dabigatran 110 2 x 1
% (n/n)
Spontaneous 25 (5/20) 14 (2/14) 20 (1/5)
Traumatic 31 (5/16) 30 (3/10) 20 (1/5)
Warfarin vs. Dabigatran 110 mg 2 x 1, p < 0,05
Warfarin vs. Dabigatran 110 mg 2 x 110, p < 0,05
Annual risk of subdural hemorrhage:
Warfarin: 0,31%/yr
Dabigatran 150 mg: 0,20%/yr
Dabigatran 110 mg: 0,08%/yr

25. BD, twice daily; ICH, intracranial haemorrhage
Hart et al. Stroke 2012;43:1511–7
In RE-LY® fewer fatal ICHs occurred with dabigatran
vs warfarin
Warfarin
Dabigatran
110 mg BD
Dabigatran
150 mg BD
Total ICH (n) Fatal ICH (n)
UK/DBG-151019c Date of preparation: April 2015
Prescribing information is available at this stand
*Despite of lack of specific treatment and antidote for dabigatran during RELY trial

26. Case history:
EHRA practical guide for use for new oral anticoagulants. Europace 2013; 15: 625-651
• Alina was admitted to ICU to monitor vital life functions
and to prepare for ELECTIVE neurosurgery
• Dabigatran was discontinued
• Fluids+diuretics were administered
• Surgery was planned ≥72h according to the guidelines
Creatinine
clearance
(mL/min)
Estimated half-life (hrs)
Stop dabigatran
High bleeding risk or major
surgery
Standard risk
≥80 ~13 2 days before 24 hours before
≥50−<80 ~15 2−3 days before 1−2 days before
≥30−<50 ~18 4 days before 2−3 days before (>48 h)

27. Case history:
• 2h later: disorientation,
LS paresis progressed
• NIHSS 7p, GCS 13p
• Brain CT
• URGENT operation planned
• aPTT 48s
• aPCC (FEIBA) 50 IU/kg iv
administered
• Clinical condition stable
• 45 min later: aPTT 33s,
subdural hematoma surgery
• 3 days later: slight LS
paresis, GCS 15p
aPCC: activated prothrombin complex concentrate

28. aPCC, activated prothrombin complex concentrate; FFP, fresh frozen plasma; PCC, prothrombin complex concentrate; rFVIIa,
recombinant Factor VIIa; Adapted from Heidbuchel H et al. Europace 2013;15:625–51
Management of bleeding on NOACs
ESC 2012 focused update
Consider
• PCC 25 U/kg;
repeat 1×/2× if
indicated
• aPCC 50 IU/kg;
max 200 IU/kg/day
• rFVIIa 90 µg/kg
Supportive measures
• Mechanical compression
• Surgical haemostasis
• Maintain hemodynamic stability
• Fluid replacement (colloids if needed)
• RBC transfusion if needed
• FFP (as plasma expander)
• Platelet transfusion
(if platelet count ≤60×109/L)
• Anti fibrinolytic agents
Additional options for dabigatran
• Oral charcoal if recently ingested
• Maintain adequate diuresis
• Consider haemodialysis
+ +
Bleeding whilst using
a NOAC
• Delay or
discontinue next
dose
• Reconsider
concomitant
medication (hold
antiplatelets)
Mild bleeding
Moderate/severe
bleeding
Life-threatening
bleeding

29. Pollack CV. J Emerg Med 2013;45:467–77; Adis Medical Writers. Drugs Ther Perspect 2013;29:77–81;
Goodnough LT. Crit Care Clin 2012;28:413–26
FFP is used in multimodal approach to bleeding management,
but has significant limitations
Fresh frozen plasma is not intended to reverse anticoagulation, but may be
indicated to expand plasma volume in patients who require massive
transfusion
Despite the benefits of FFP for patient management, it is associated with
significant limitations
Risk of intravascular volume
overload and heart failure Slow: thawing, transfusion, and ABO
cross-matching
Short duration of action
 Quantities of Vitamin K-dependent
coagulation factors vary
FFP = fresh frozen plasma

30. Logan AC & Goodnough LT. Hematology Am Soc Hematol Educ Program Book 2010;2010:153–9; NovoSeven®: EU SPC,
2012 (available at http://www.medicines.org.uk/emc/); NovoSeven®: US PI, 2012 (available at http://www.novo-
pi.com/novosevenrt.pdf); Pradaxa®: EU SPC, 2014; Heidbuchel H et al. Europace 2013;15:625–51
rFVIIa is used extensively off-label for emergency bleeding
management, although data on clinical utility are limited
Approved for treatment or prevention of bleeding in patients with
conditions such as haemophilia or congenital Factor VII deficiency
EU label suggests consideration of rFVIIa for bleeding management
Potential risk for rebound thromboembolism

EHRA states rFVIIa needs further evaluation before it can be
recommended for bleeding management

31. Heidbuchel H et al. Europace 2013;15:625–51; van Ryn J et al. Blood 2011;118:abstr 2316; Weitz J et al. Circulation
2012;126:2428–32; Pollack CV. J Emerg Med 2013;45:467–77;
PCCs/aPCCs show promise for reversing anticoagulant effects
of NOACs, but have limitations in practice
Emerging animal and human data support the use of PCC and
aPCC for reversal of NOACs
Consensus expert opinion suggests consideration of PCC and
aPCC in patients with moderate to severe bleeding
Can ‘overshoot’ and enhance thrombin generation parameters to
supra-normal levels (more prominent with FEIBA® vs unactivated PCCs),
which may result in over-coagulation

Limited correlation between the haemostatic effects of PCCs and
their effect on conventional laboratory assays
PCC and aPCC products are not uniform

aPCC, activated prothrombin complex concentrate; FFP, fresh frozen plasma; PCC, prothrombin complex concentrate

32. *Based on limited nonclinical data only
This information is not intended and must not be considered as a specific recommendation from Boehringer Ingelheim
FEIBA, factor eight inhibitor bypass activity
Weitz J et al. Circulation 2012;126:2428–32
Experience from McMaster: life-threatening bleeding
ICH or life-threatening bleeding
Administer FEIBA (50 IU/kg)
If unavailable, give PCC (40 IU/kg)
or rFVIIa (90 μg/kg)*
Generally preferable
to wait at least 30 min
to assess the effect of
each therapy before
initiating the next
• *If bleeding cannot be managed
(haemodynamically unstable, renal
impairment), consider
haemodialysis for 6–8 hours or
charcoal filtration
• Monitor aPTT and/or Hemoclot®
every 3 hours
• *Consider procoagulants:
start with PCC (40 IU/kg)
• If bleeding continues,
give FEIBA (50 IU/kg)
• If bleeding continues,
give rFVIIa (90 μg/kg)

33. Would a specific antidote provide an additional therapeutic option ?
Most patients respond to supportive measures and
withholding of the anticoagulant, which has a short half-life
Only a minority of patients will require an antidote
Life-threatening bleeding Emergency surgery

34. The antidote is still under investigation and has not yet been approved for clinical use
Glund S et al. Presented at AHA 2013;17765
Idarucizumab is currently under investigation:
Shows potential as a true, specific antidote to dabigatran
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 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

35. 1-year follow-up data from subgroup of patients with AF (n=566)
AF atrial fibrillation; CI, confidence interval; HR, hazard ratio; ICH, intracranial haemorrhage; OAC, oral anticoagulant
Kuramatsu et al. JAMA 2015
Despite experiencing an ICH on OAC, re-starting anticoagulation
should be assessed in patients with AF
0
5
10
15
20
OAC No OAC
Fewer ischaemic complications
Patients(%)
(P=0.008)
5.5% vs 14.9
Decreased mortality
risk
0
10
20
30
40
OAC No OAC
Patients(%)
HR: 0.26
95% CI: 0.13–0.53
8.3% vs 30.7%

36. Restarting anticoagulation after ICH ?
Enfo RC et al. CCJM 2010,11
Factor Pro* Contra
High embolic risk (CHADS2≥3) X
Valvular AF / mechanical valves (VKA) X
Post-traumatic ICH – low recurrent risk ? X
Deep/hypertensive ICH (BP well controlled) X
Spontaneous ICH (no risk factors) X
Lobar ICH X
Amyloid angiopathy [genotype ApoE ? ] X
Multiple microbleeds in MRI (>5 ? ) X
Patient non compliance X
* after good control of vascular risk factors is achieved (f.e. BP !)
* ICH during VKA  NOACs

37. Steiner T et al. Int J Stroke 2014;9:840–55
Furie K et al Stroke 2012
Morgenstern A et al. Stroke 2010 LAA = left atrial appendage
Post-acute phase, looking to the guidelines…
Prevention of Stroke in Patients with Stroke or TIA
Intracerebral Hemorrhage Guideline
• Lack of clinical data to guide re-initiation of anticoagulant. Suggested
restarting after ≥14 days to 30 weeks. (Class IIb; Level of Evidence:B)
• Anticoagulation after nonlobar ICH might be considered,
particularly when there are definite indications for these agents (IIb, B)
• It is reasonable to consider risk factors for recurrence: lobar location
of the initial ICH, older age, presence of the Apo E2/4, number of
microbleeds on MRI (IIa; B).
• After lobar ICH anticoagulation should be avoided (IIa, B)
• Alternatives such as LAA occlusion may be an option for patients at
high risk of cardioembolic stroke (IIb,B)

38. LAA = left atrial appendage
Percutaneous LAA Occlusion
The WATCHMAN® Device
Syed T, Halperin JL. Nature Clin Prac Cardiovasc Med 2007; 4:428
Holmes DR, et al. Lancet 2009; 374: 534

39. Clinical benefit with DBG treatment outweighs risk in high
bleeding risk patients
Banerjee A i wsp. Thromb Haemost 2012; 107
Neurology 2014;82:716–724
AAN Recommendations (2014)
Clinicians might offer oral anticoagulation to patients with
NVAF who have dementia or occasional falls. (Level B).
Clinicians should administer NOACs to patients requiring
anticoagulation who are at higher risk of intracranial
bleeding [IIa,B]

40. „It’s good to live in times when medicine has made
such a substantial progress”