discuss management of bleeding in patient with oral anticoagulant for stroke prevention atrial fibrillation.

1. Faris Basalamah, MD

2. 1. Chowdhury P, et al. Cleve Clin J Med. 2009;76:543–550; 2. Savelieva I et al. Ann Med 2007;39:371-391; 3. Atrial Fibrillation
Investigators. Arch Intern Med 1994;154:1449-1457 ; 4. Hannon N et al. Cerebrovasc Dis 2010;29:43–9; 5. Emmerich J et al. Eur Heart J
Atrial fibrillation define as a
supraventricular arrhythmia characterized by
chaotic and uncoordinated contraction of
the atrium1
Atrial Fibrillation (AF) is associated
with a 5-fold higher stroke risk
overall2
Without prevention, approximately 1 in
20 patients will have a stroke each
year3
Responsible for nearly a third of all
strokes4
The leading cause of embolic stroke5
Have worse prognosis than those with
a stroke unrelated to AF5
Burden of Atrial Fibrillation :

3. Based on data collected in the Danish National Indicator Project for 39 484 patients hospitalized for stroke
(80% of all stroke admissions in Denmark) including 6294 patients with AF); OAC use not recorded
Andersen KK et al. Stroke 2009;40:2068–72
Types of stroke in patients with AF
Ischaemic
92%
(n=5810)
Haemorrhagic
8%
(n=484)

5.  3 types Anticoagulant
◦ Vitamin K Antagonis
warfarin
◦ Direct Thrombin Inhibitors
Dabigatran
◦ Factor Xa Inhibitors
Rivaroxaban, Apixaban, Edoxaban

7. Hein heidbuchel et al, EHRA practical guidelines on the use of NOAC. Europace (2013)15, 625-651

8. Warfarin
n=6022
Dabigatran
150 mg BID
(P value vs
warfarin)
n=6076
Dabigatran
110 mg BID
(P value vs
warfarin)
n=6015
Major bleeding 3.57 3.32
(0.31)
2.87
(0.003)
– Life-threatening 1.85 1.49
(0.03)
1.24
(<0.001)
– Non-life threatening 1.92 2.06
(0.39)
1.83
(0.65)
– Gastrointestinal 1.07 1.56
(0.001)
1.15
(0.52)
Data are %/year
Connolly SJ et al. N Engl J Med 2010;363:1875–6

14. Stroke & Death Risk Assesment
in AF Patients : CHA2DS2-VASc
Risk factor score
C Congestive heart failure/LV dysfunction 1
H Hypertension 1
A2 Age ≥75y 2
D Diabetes mellitus 1
S2 Stroke/TIA/TE 2
V
Vascular disease (prior myocardial infarction,
peripheral artery disease, or aortic plaque)
1
A Age 65-74y 1
Sc Sex category (ie female gender) 1
Maximum Score 9
Lip GY, et al. Chest 2010;137:263-272
maximum score is 9 since age may contrubute 0, 1, or 2 points

15. Bleeding Risk Prediction Score in AF
Patients
HAS-BLED Score
Hypertension (SBP>160mmHg) 1
Abnormal renal or liver function (1 point each) 1 or 2
Stroke 1
Bleeding (history or predisposition) 1
Labile INRs (e.g.< 60% TTR) 1
Elderly (e.g. age >65yrs) 1
Drugs or alcohol
(1point each; includes antiplatelets and NSAIDs)
1 or 2
INR = International normalized ratio; NSAID = non-steroidal anti-inflammatory drug;
SBP = systolic blood pressure; TTR = time in therapeutic range
Camm J et al. Eur Heart J 2010;31:2369–429

16. Atrial fibrillation
Valvular AF*
Assess risk of stroke
CHA2DS2-VASc score
No antithrombotic
therapy
NOAC VKA
0 1
No (i.e. nonvalvular)
Yes
≥2
Oral anticoagulant therapy
<65 years and lone AF (including females)
Assess bleeding risk (HAS-BLED score)
Consider patient values and preferences
 to choose right dose
No
Yes
Recommended Optional
Camm AJ et al. Eur Heart J doi:10.1093/eurheartj/ehs253
No room for antiplatelet

18. OR for 30-day mortality adjusted for sex, age, weight, renal function, and additional antithrombotic therapy
CI = confidence interval; OR = odds ratio
Majeed A et al. Circulation 2013;128:2325–32
Favours dabigatran Favours warfarin
10.1 10
0.66 (0.44–1.00)
0.60 (0.35–1.03)
0.56 (0.36–0.86) 0.009
0.051
P valueOR (95% CI)Treatment and database used
Dabigatran 150 mg + 110 mg, all studies
Dabigatran 110 mg, RE-LY®
Dabigatran 150 mg + 110 mg, RE-LY®
Adjusted analysis demonstrates significant mortality benefit for
dabigatran in RE-LY®
0.65 (0.38–1.11)Dabigatran 110 mg, all studies
0.68 (0.42–1.08)Dabigatran 150 mg, all studies
0.52 (0.31–0.88)Dabigatran 150 mg, RE-LY®

19. Bleeding definitions
Consensus statement on management of dabigatran-induced bleeding1
Mild bleeding Severe bleeding
Life-threatening or
organ-threatening bleeding
• No transfusion
• Stable haemodynamics
• <4 erythrocyte concentrates
• Haemodynamically stable without
catecholamines
• ≥4 erythrocyte concentrates
• Catecholamine demand
Bleeding definitions in the RE-LY® trial2
Minor bleeding Major bleeding Life-threatening bleeding
Clinical bleeding that does not fulfil
the criteria for major bleeds
Bleeding associated with one or
more of the following:
• Hb ≥2.0 g/L
•transfusion of ≥2 U blood or packed
cells
•symptomatic bleeding into a critical
organ*
Bleeding associated with one or
more of the following:
•fatal, symptomatic intracranial
bleeding
• Hb ≥5.0 g/L
•transfusion of ≥4 U blood or packed
cells
•hypotension requiring IV inotropic
agents
•necessitating surgical intervention
*Intraocular, intracranial, intraspinal, or intramuscular with compartment syndrome, retroperitoneal, intra-articular or
pericardial; Hb = haemoglobin; IV = intravenous; U = unit
1. Fries D et al. Wien Klin Wochenschr 2013;125:721–9; 2. Ezekowitz MD et al. Am Heart J 2009;157:805–10

22. Haemodialysis for dabigatran elimination
 Dabigatran can be dialysed because:
 it has low plasma protein binding (~30%)1,2
 it is highly water soluble1
 A Phase I study concluded that haemodialysis may
be a suitable approach for elimination of dabigatran
in emergency situations2
 ~50–60% dabigatran concentrations were removed
over
4 hours
 Haemodialysis removes the drug and may
effectively accelerate total clearance, especially in
patients with impaired kidney function3
1. Stangier J et al. Thromb Haemost 2009;15:9S–16S; 2. Khadzhynov D et al. Thromb Haemost 2013;109:596–605; 3. Singh T et
al. Clin J Am Soc Nephrol 2013; 8:1533–9

23. Case reports of successful elimination of
dabigatran by dialysis are emerging
Setting Outcomes
Life-threatening bleeding
(7 consecutive cases)1
Dabigatran concentrations decreased
Removal prior to surgery:2–4
haematoma, ileostomy,
heart transplantation
No unexpected bleeding events associated with
surgery
Pulmonary haemorrhage after
unintentional overdose5
Bleeding stopped and patient improved clinically
GI and surgical site bleeding6 Patient slowly benefited with continuous dialysis
GI bleeding7 Haemoglobin and haematocrit stabilized after
plasmapheresis
GI bleeding8 No further bleeding events during hospitalization
Severe ICH9 Dabigatran levels decreased
Severe bleeding following cardiac
surgery10
Dabigatran levels decreased quickly and bleeding
subsided
23
1. Kumar R et al. J Intensive Care Med 2014; doi: 10.1177/0885066614527417; 2. Esnault P et al. Br J Anaesth 2013;111:776–7; 3. Babilonia K et al. Am J
Hematol 2012;87:S177; 4. Wanek MR et al. Ann Pharmacother 2012;46:e21; 5. Chen BC et al. Am J Kidney Dis 2013;62:591–4; 6. Harinstein LM et al J
Pharm Pract 2013;26:
264–9; 7. Kamboj J et al. Am J Ther 2012;19:e182–5; 8. Wychowski MK, Kouides PAl. Ann Pharmacother 2012;46:e10; 9. Chang DN. Am J Kidney Dis
2013;61:487–9; 10. Warkentin TE et al. Blood 2012;119:2172–4

24. Life-threatening bleeding:
additional options for consideration
 Charcoal filtration1
 Consideration of rFVlla or PCC1
24
1. van Ryn J et al. Thromb Haemost 2010;103:1116–271 (recommendation based only on limited non-clinical data; no experience
in volunteers or patients); 2. Dager WE et al. Crit Care Med. 2013;41:e42–6; 3. Dumkow LE et al. Am J Health Syst Pharm.
2012;69:1646–50; 4. Javedani PP et al. Am J Crit Care. 2013;22:169–76; 5. Diaz MQ et al. Haematologica 2013;98:e143; 6.
Warkentin TE et al. Blood 2012;119:2172–4
Individual case studies of patients receiving dabigatran have reported the successful
use of:
low-dose FEIBA (activated PCC) to restore haemostasis in a patient who suffered
perforation and cardiac tamponade during an AF ablation procedure2
PCC and fresh frozen plasma in a patient with haemorrhagic shock secondary to
upper GI bleeding3
PCC and rFVIIa in a patient with possible ICH associated with an acute ischaemic
stroke4
PCC in patients with AF experiencing GI bleeding5
high-dose rFVIIa and haemodialysis in a patient with bleeding following elective
cardiac surgery6

26. Assess renal function
26
Renal function
(CrCl mL/min)
Dabigatran half-life
(hours)
≥80 ~13
≥50–<80 ~15
≥30–<50 ~18
≤30 27
Clearance of dabigatran may take longer in patients with
renal impairment
Note that dabigatran is contraindicated in patients with severe renal impairment (CrCl <30 mL/min)
Pradaxa®: EU SmPC, 2013

27. Time of last NOAC dose should always be considered when interpreting test results
aPTT, activated partial thromboplastin time; dTT, diluted thrombin time; ECT, ecarin clotting time; FXa, activated Factor X;
PT, prothrombin time. Adapted from: Heidbuchel et al. Europace 2015; Pradaxa®: EU SPC, 2016; Xarelto®: EU SPC;
Eliquis®: EU SPC; Lixiana®: EU SPC
Dabigatran Rivaroxaban Apixaban Edoxaban
aPTT
TT
dTT, ECT
Anti-FXa assays
PT
INR

Specific calibrators should be used with PT and anti-FXa assays
due to differences with reagents




  
















Green = quantitative; orange = qualitative only; red = not applicable
Which coagulation assay should be used?Which coagulation assay should be used?

28. Interpretation of Coagulation Test for
NOAC

29. Which coagulation assay should be
used?
29
aPTT
ECT
TT
dTT
(e.g. Hemoclot®)
Normal result indicates minimal or no
clinically relevant anticoagulant effect
Trough measure of ≥200 ng/mL is
associated with a higher risk of bleeding
I need to know whether
dabigatran is present or not
I need to know the plasma level
of dabigatran
Do not use INR
Not sufficiently sensitive, point-of-care devices have shown falsely elevated values
dTT = dilute thrombin time
Pradaxa®: EU SmPC, 2013; van Ryn J et al. Thromb Haemost 2010;103:1116–27

30. aPCC, activated PCC; PCC, prothrombin complex concentrate; rFVIIa, recombinant activated Factor VII
Tran et al. Intern Med J 2014; Weitz et al. Circulation 2012; Rossaint et al. Critical Care 2016
Non-specific measures to overcome/reverse the anticoagulant
effect of NOACs are available but have limitations
Stop medication/wait,
maintain diuresis
Takes valuable time
Sufficient renal function
needed
Activate coagulation to
overcome effects of the drug
(PCC, aPCC, rFVIIa)
Potential prothrombotic risk
PCC is not specific and
not immediate-acting
Uncertain benefit
Remove drug with dialysis
(only for dabigatran)
Requires infrastructure
and time
Difficult if haemodynamically
compromised

31. Idarucizumab PER977
Andexanet
alpha
Structure
Humanized
Fab fragment
Synthetic small
molecule
Human
rXa variant
Target Dabigatran Universal FXa inhibitors
Binding
Non-competit.
High affinity
? Competitive
Clinical studies
Rapid
complete
reversal
?
Rapid, near
complete
reversal

32. Where might specific NOAC reversal agents be used?
Urgent
surgical
intervention
(acute abdomen)
or GI bleed
Bone fracture
(hip, femur,
open extremity,
other)
Infection
(joint, sepsis,
abscess)
Incarcerated
hernia
ICH
Urgent invasive
procedures
(neurosurgery)
Urgent
lumbar
puncture
Acute renal
failure,
obstruction
Urgent CABG
Heart transplant
Complications of AF
ablation/PCI
Pacemaker implant
Urgent cardiac
surgery
CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention

33. D110, dabigatran 110 mg BID, D150, dabigatran 150 mg BID
1. Douketis et al. Thromb Res 2016; 2. Connolly et al. N Engl J Med 2014
Anticoagulated patients may experience life-threatening
bleeding or require urgent surgery
2.0%
required urgent surgery
or procedures1
Life-threatening
bleeding reported for:2
1.2% on D110
1.5% on D150
1.9% on warfarin
In RE-LY®…

34. Schiele et al. Blood 2013; Glund et al. Thromb Haemost 2015
Idarucizumab was designed as a specific reversal agent
for the anticoagulant activity of dabigatran
Dabigatran
Idarucizumab
Humanized Fab: binds free dabigatran and
dabigatran bound to thrombin
No known off-target effects; does not reverse
heparins or any other anticoagulants
Binding affinity for dabigatran ~350× higher than
dabigatran for thrombin
IV administration,
immediate onset of action
Short half-life
No intrinsic procoagulant or anticoagulant activity
Idarucizumab is currently not available in Indonesia. The
information presented here is intended for medical education
purposes only

35. Multicentre, open-label, single-arm, Phase III study
Group A:
Uncontrolled bleeding
+ dabigatran-treated
Group B:
Emergency surgery or
procedure +
dabigatran-treated
N=494
0–15 min 90 days’ follow-up
Hospital
arrival
5 g idarucizumab
(2×2.5 g intravenously)
Pre-2nd vial 2 h 4 h 12 h 24 h 30 d 90 dPre-1st vial 1 h
Blood
samples
*Connolly et al. N Engl J Med 2009; Pollack et al. Thromb Haemost 2015;
Pollack et al. AHA 2016
ECT, ecarin clotting time
~20 min
Reverses up to the 99th percentile of
dabigatran levels measured in RE-LY®*
Primary endpoint: Maximum reversal
within 4 hours based on dTT, ECT

36. 53%
14%
33% 33%
20%
Assessable
non-ICH
Non-assessable
non-ICH
ICH
GI
Non-GI
*Local investigator-determined time to bleeding cessation
Pollack et al. AHA 2016
Group A: bleeding stopped within 3–5 hours in patients with
extracranial haemorrhage
298 patients with bleeding
type classed as:
Median time* to
bleeding cessation
3.5 hrs
Group A
4.5 hrs

37. Pollack et al. AHA 2016
Group B: most patients had normal haemostasis
during surgery
2%
93%5% Normal
Mildly
abnormal
0% Severely
abnormal
1.6 hrs
Overall median time
from first vial to
procedure
Moderately
abnormal
191/196 (97.4%) patients
underwent surgery/procedure
with periprocedural haemostasis
classed as:
Group B

39.  No doubt oral anticoagulant is very important for AF patients
 NOAC has lower or same risk of bleeding compare with VKA
 We have to know the property of NOAC that we gave to our patients in case of
bleeding to our patients
 If a bleeding event does occur, patients can often be managed using standard
measures
 Factor concentrates or haemodialysis may also be used to reverse the effects of
dabigatran (based on limited clinical experience)
 In the future, idarucizumab, a dabigatran-specific antidote, or other antidotum of
other NOAC will provide an additional option for the management of emergency
bleeding in patients taking dabigatran

41. Thanks

42. Coagulation assays
42
aPTT*
• Normal aPTT = pharmacologically relevant anticoagulation is low
• >2-fold prolongation at trough → higher bleeding risk
– Provides an approximate indication of the anticoagulation intensity
– Limited sensitivity, particularly at high plasma concentrations of dabigatran
– ~1.5-fold prolongation at trough expected after 150 mg BID
– May show false prolonged measures in the first 2–3 days after surgery
– May be prolonged by heparin and its derivatives
– Manufacturer-dependent differences in sensitivity
ECT
• Normal ECT = pharmacologically relevant anticoagulation is low
• >3-fold prolongation at trough → higher bleeding risk
– Provides a direct measure of the activity of dabigatran
TT • Normal TT = no clinically relevant anticoagulant activity
dTT
• A trough dTT >200 ng/mL → higher bleeding risk
– Provides an estimation of dabigatran concentration that can be compared with expected
plasma concentrations
Semiquantitative (may be prone to interlaboratory variability)
Quantitative
*Sensitivity of aPTT may vary, dependent on manufacturer; generation of in-house reference values is recommended
Pradaxa®: EU SmPC, 2013; van Ryn J et al. Thromb Haemost 2010;103:1116–27

43. Incidence of ICH Independent risk factor :
Overal rate incidence of ICH 0.67% per 100 patients-year, with fatality rate 49%
No different between warfarin and Rivaroxaban

44. Managing bleeding in patients treated with
dabigatran: general care
Apply same measures as for patients treated with VKAs
excluding Vitamin K application
Discontinue dabigatran and investigate source of bleeding
Maintain adequate diuresis
and initiate standard treatments
VKA = Vitamin K antagonist
Pradaxa®: EU SmPC, 2013; van Ryn J et al. Thromb Haemost 2010;103:1116–27

45. Managing bleeding complications in patients
treated with dabigatran
Patient with bleeding on dabigatran therapy
Mild bleeding Moderate to severe bleeding
Life-threatening
bleeding
Delay next dose or
discontinue treatment
as appropriate
• Symptomatic treatment
• Mechanical compression
• Surgical intervention
• Fluid replacement and
haemodynamic support
• Blood product transfusion
• Haemodialysis
• Oral charcoal application*
(if dabigatran ingested <2 hours
before)
• Consideration of
rFVlla or PCC*
• Charcoal filtration*
A specific antidote may provide an additional option for patient
management during emergency situations
*Recommendation based only on limited non-clinical data; no experience in volunteers or patients
PCC = prothrombin complex concentrates (non-activated or activated); rFVIIa = recombinant Factor VIIa
van Ryn J et al. Thromb Haemost 2010;103:1116–27

48. Levy et al. J Thromb Haemost 2016
When should we consider reversing anticoagulation?
• Life-threatening (e.g. intracranial)
• Critical organ (e.g. intraocular) or closed space
(e.g. retroperitoneal, pericardial)
• Ongoing (despite measures to control bleeding)
In a patient experiencing bleeding:
In a patient requiring emergency surgery/urgent procedure
e.g. urgent cardiac surgery or neurosurgery, acute abdomen
Idarucizumab is currently not available in Indonesia. The information presented here is intended for medical
education purposes only

49. Managing emergency room patients who have
taken dabigatran etexilate
 Which dose did they take?
 When was the last dose
taken?
Take patient
history
Assess
coagulation
status and renal
function
Use test results
to help guide
treatment
decisions
Which coagulation assay to use?
What is the impact of their renal
function?
What supportive measures are
needed?

51. Immediate anticoagulant reversal, if it is ever needed
Road accident?
Fall? Trauma?
Patient with AF
started on OAC
Urgent
surgery?
Cardiac
emergency?
!

52. Mild bleeding: management options for
consideration
*Dependent on:
•factors influencing plasma concentrations (e.g. strong P-glycoprotein inhibitors, chronic kidney disease)
•factors influencing haemostasis (e.g. concomitant use of antiplatelet drugs)
van Ryn J et al. Thromb Haemost 2010;103:1116–27; Heidbuchel H et al. Europace. 2013;15:625-51
Discontinue dabigatran
Restoration of haemostasis is to be
expected within 12–24 hours*
Due to the short half-life of dabigatran, in most cases drug
discontinuation is sufficient to manage any anticoagulant-related bleeding

53. Moderate to severe bleeding:
additional options for consideration
*Recommendation based only on limited non-clinical data; no experience in volunteers or patients
van Ryn J et al. Thromb Haemost 2010;103:1116–27
Moderate/severe
bleeding
Symptomatic
treatment/mechanical
compression
Surgical intervention
Oral charcoal application*
(if dabigatran ingested
<2 hours before)
Blood product transfusion
Haemodialysis
(see next 2 slides)
Fluid replacement and
haemodynamic support

54. Evaluate anticoagulant activity
 Close correlation between plasma concentration of dabigatran and
anticoagulant response
 Response strongly depends on the time the blood sample was taken
relative to the last dose; therefore, note time of last dose where possible
55
aPTT = activated partial thromboplastin time; ECT = ecarin clotting time; INR = international normalized ratio;
TT = thrombin time
Pradaxa®: EU SmPC, 2013; van Ryn J et al. Am J Med 2012;125:417–20;
Stangier J et al. Br J Clin Pharmacol 2007;64:292–303

55. Conclusion
 Dabigatran has been shown to have a favourable safety profile compared with
warfarin
 Understanding coagulation activity of dabigatran may be useful in emergency
circumstances, such as bleeding
Idarucizumab is currently not available in Indonesia. The information presented here is intended for medical
education purposes only