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ACS and Thrombosis in the
Emergency Setting
ER Direct Case:
Management of Atrial Fibrillation and PostTreatment Bleeding in Patient with Prior TIA
Faculty/Presenter Disclosure
 Faculty: Andre Douen, MD,PhD,FRCPC,FAHA
 Relationships with commercial interests:
 Grants/Research Support: None that relates to current presentation
 Speakers Bureau/Honoraria: Boehringer-Ingelheim, BMS, Sanofi-Aventis
 Consulting Fees: Ad boards: Boehringer-Ingelehim, BMS, Sanofi-Aventis
 Other: CMO and Co-Chief editor ‘eDucate’ web portal
www.educatehealth.ca
Disclosure of Commercial Support
 This program has received financial support from Astra Zeneca
and Boehringer-Ingelheim in the form of an educational grant.
 This program has received in-kind support from CAEP in the
form of logistical support.
 Potential for conflict(s) of interest:


Dr. Douen has received an honorarium from for this program,
supporting this program AND/OR organization whose product(s) are
being discussed in this program].
Boehringer-Ingelheim will benefit from a product that will be
discussed in this program: Pradaxa/dabigatran.
Mitigating Potential Bias
 “While I have received an honoraria from for this program,
and discuss dabigatran/Pradaxa from Boehringer Ingelheim, the
information presented provides an unbiased overview of all
products related to treating patients”.
Stroke in AF patients
 Atrial fibrillation (AF) affects over 350 000 Canadians.
 The risk of developing AF increases with age and with other risk
factors such as diabetes, high blood pressure, and underlying
heart disease.
 One of the main complications of AF is stroke. Individuals with
AF have a risk of stroke that is 3 to 5 times greater than those
without AF.
 Heart disease and stroke cost the Canadian economy more than
$20.9 billion every year in physician services, hospital costs, lost
wages and decreased productivity.
http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.5052135/k.15A/Atrial_fibrillation.htm?utm_campaign=offline&utm_source=bepulseaw
are&utm_medium=vanit
New Oral Anticoagulants
 Dabigatran:

Prevention of stroke and systemic embolism in AF patients (150mg BID and
110mg BID) with lower dose available for AF patients over 80y or any AF
patient with higher risk of bleeding.

Prevention of VTE in total hip and knee replacement (2x 110mg or 2x 75mg
capsules OD) with lower dose available for consideration in TKR/THR patients
over 75y.
 Rivaroxaban:

Prevention of stroke and systemic embolism in AF (15mg and 20mg)

DVT treatment / prevention of recurrent DVT and PE (15mg and 20mg); and
prevention of VTE in total hip and knee replacement (10mg).
 Apixaban:

Prevention of stroke and systemic embolism in AF (5mg BID)

VTE in elective hip or knee replacement (2.5mg BID)
http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.5052135/k.15A/Atrial_fibrillation.htm?utm_campaign=offline&utm_source=bepulseaw
are&utm_medium=vanit
Patient Presentation
 Mike is a 59-year-old male.
 He presents to the emergency department complaining of
heart palpitations, dizziness and sweating.

“I’ve had this before, but boy, this time it’s really intense, and
it’s not going away.”
 About 1 week ago Mike had a “spell”. While eating dinner he
suddenly stopped speaking, the right side of his mouth
drooped, the fork fell from his hand. This episode lasted
20 minutes. Mike did not go to the ED.

“I felt fine and was about to go on a trip.”
Medical History
Previous conditions:
Lifestyle:
 Mike was diagnosed with AF
 Mike is married and lives with his
3 years ago and is currently on
warfarin.
 His INR has been stable although
he admits that the monitoring is
difficult because of his lifestyle
and work-related activities.
 His INR one week ago was 1.5.
 Hypertension, managed with
ramipril and a thiazide.
 Diabetes, managed with
metformin.
wife, who accompanies him today.
 He works from home, job is stressful,
and frequently travels to the US for
business.
 He goes to the gym twice a week.
 Smokes 8-9 cigarettes/day,
especially when he is travelling.
 Drinks 3-4 glass of wine or beer/day.
 This increases to 5-6glasses of wine
or beer/day when he is travelling
(about once/month).
Physical Examination and Labs
 Height 5’11’’ (180 cm), weight 187 lbs (85 kg), BMI is 26.1 .
 12-lead ECG results confirm AF
 Kidney and liver function: normal
 Physical examination: Consider excluding a deficit which would
suggest stroke.


Speech, motor function, facial strength, visual fields
BP (correlates with risk of hemorrhage)
 The neurological episode was focal, abrupt in onset and brief.


It meets the clinical diagnosis of TIA
New criteria require the exclusion of tissue damage with brain
imaging
 Imaging / investigations: Consider excluding other causes of TIA
and exclude rare mimics.

CT head, carotid Doppler or CTA/MRA
Canadian Best Practice Recommendations for Stroke Care (Update 2010) - http://www.hsf.sk.ca/siss/documents/2010_BP_ENG.pdf
Management Options
 Options for management include:


Remain on warfarin with more frequent INR determinations OR
Switch to one of the new OAC agents
OAC AGENT
Apixaban
STANDARD DOSE
5 mg BID
Dabigatran
150 mg BID
Rivaroxaban
20 mg QD
LOWER DOSE
2.5 mg QD in patients with at least 2 of the following
characteristics: age ≥80 years, weight ≤60 kg, or Serum
creatinine ≥1.5 mg/mL
110 mg BID for patients ≥80 years or patients ≥75 years
with a risk factor for bleeding
15 mg QD in patients with CrCl 30-49 mL/min
 Management options must be selected in context of :





Good control of blood pressure and diabetes
Lifestyle and risk factor management
Lipid lowering (a candidate for statins)
Evaluation of stroke risk using CHADS2, CHA2DS2-VASc, and
bleeding risk using HAS-BLED
Creatinine clearance (see dosage indications for each agent)
The use of NOAC post stroke or post TIA
 Apixaban: Contraindicated with recent cerebral infarction.
 Dabigatran: Contraindicated with recent extensive cerebral
infarction. DATAS trial is underway investigating dabigatran
post TIA and minor stroke:
http://clinicaltrials.gov/show/NCT01769703
 Rivaroxaban: Contraindicated with recent cerebral
infarction.
CHADS2 Score
(Simple Prediction Tool for Assessing Stroke Risk)
1 POINT for Congestive Heart Failure
1 POINT for Hypertension
1 POINT for Age ≥ 75 years
1 POINT for Diabetes Mellitus
2 POINTS for Prior Stroke or TIA
CHADS2 SCORE*
STROKE RATE, %/YR
(95 %CI)
0
1.9 (1.2 – 3.0)
1
2.8 (2.0 – 3.8)
2
4.0 (3.1 – 5.1)
3
5.9 (4.6 – 7.3)
4
8.5 (6.3 – 11.1)
5
12.5 (8.2 – 17.5)
6
18.2 (10.5 – 27.4)
*Score 0: Patients can be administered aspirin
*Score 1: Patients can be administered aspirin or anticoagulant therapy
*Score ≥2: Patients should be administered anticoagulant therapy
Gage BF, et al. JAMA. 2001;285:2864-2870.
CHA2DS2-VASc Score
Novel Stroke Risk Stratification Tool,
Complements CHADS2
1 POINT for Congestive Heart Failure/
LV Dysfunction
1 POINT for Hypertension
2 POINTS for Age ≥ 75 years
1 POINT for Diabetes Mellitus
2 POINTS for Prior Stroke or TIA1 or TE2
1 POINT for Vascular Disease3
1 POINT for Age 65-74 years
1 POINT for Sex category (female gender)
CHA2DS2-VASc
SCORE*
ONE YEAR EVENT RATE (95% CI) OF HOSPITAL
ADMISSION AND DEATH DUE TO
THROMBOEMBOLISM† PER 100 PERSON YEAR
0
0.78 (0.58 – 1.04)
1
2.01 (1.70 – 2.36)
2
3.71 (3.36 – 4.09)
3
5.92 (5.53 – 6.34)
4
9.27 (8.71 – 9.86)
5
15.26 (14.35 – 16.24)
6
19.74 (18.21 – 21.41)
7
21.5 (18.75 – 24.64)
8
22.38 (16.29 – 30.76)
9
23.64 (10.62 – 52.61)
*Score 0: Patients can be administered aspirin
*Score 1: Patients can be administered aspirin or anticoagulant therapy
*Score ≥2: Patients should be administered anticoagulant therapy
†Includes peripheral artery embolism, ischemic stroke, and pulmonary embolism
1TIA
= Transient ischemic attack; 2TE = Thromboembolism; 3Prior myocardial infarction, peripheral artery disease, aortic plaque
1. Lip GY et al. Chest 2010;137:263-272 2. Olesen JB, et al. BMJ 2011;342:d124
3. Task Force or the Management of Atrial Fibrillation of the ESC. Eur Heart J 2010;31:236902429
HAS-BLED Bleeding Score
(Simple Tool for Assessing Bleeding Risk)
LETTER
CLINICAL CHARACTERISTIC*
POINTS AWARDED:
SCORE
H
Hypertension
1
A
Abnormal renal or liver function (1 point each)
1 or 2
S
Stroke
1
B
Bleeding
1
L
Labile INRs
1
E
Elderly
1
D
Drugs or alcohol (1 point each)
1 or 2
*Hypertension - uncontrolled, >160 mm Hg systolic; Abnormal renal/liver function (one point for presence of renal or liver impairment,
maximum two points); Stroke (previous history, particularly lacunar); Bleeding history or predisposition (anemia); Labile international
normalized ratio (INR) (i.e. therapeutic time in range < 60%); Elderly ( >65 years); Drugs/alcohol concomitantly (antiplatelet agents,
nonsteroidal anti-inflammatory drugs; one point for drugs plus one point for alcohol excess, maximum two points).
1. Pisters R, et al. Chest 2010; 138(5):1093–1100
HAS-BLED Bleeding Score
(Simple Tool for Assessing Risk of Major Bleeding within
1 Year in Patients with AF Enrolled in the Euro Heart Survey)
RISK FACTOR SCORE
MAJOR BLEEDS (%/YR)
0
1.13
1
1.02
2
1.88
3
3.74
4
8.70
5
12.50
1. Pisters R, et al. Chest 2010; 138(5):1093–1100
What are Mike’s Scores?
CHADS2 score = 4
CHA2DS2-VASc Score = 4
HAS-BLED Score = 4
1pt for hypertension,
1pt for diabetes,
2pts for prior TIA
1pt for hypertension,
1pt for diabetes,
2pts for prior TIA
1pt for hypertension,
1pt for stroke,
1pt for labile INR,
1pt for alcohol
Stroke risk management:
Score ≥1:
Patient should receive
anticoagulant therapy
Stroke risk management:
Score ≥2:
Patient should receive
anticoagulant therapy
Bleeding risk:
8.70% / year
CCS 2012 Update to AF Guidelines
Assess Thromboembolic Risk (CHADS2)
CHADS2 = 0
OAC = Oral anticoagulant
ASA = Aspirin
CHADS2 = 1
CHADS2 ≥ 2
INCREASING STROKE RISK
No antithrombotic
ASA
OAC*
OAC*
OAC
No additional
risk factors for
stroke
Either female
sex or vascular
disease
Age ≥ 65 yrs
or combination
of female sex
and vascular
disease
*Aspirin is a
reasonable
alternative in
some as
indicated by
risk/benefit
Consider stroke risk vs. bleeding risk
Only when the stroke risk is low and
bleeding risk is high does the risk/benefit
ratio favour no antithrombotic therapy
CCS 2012 Recommendation: All patients with AF [paroxysmal, persistent or permanent] or atrial flutter should be stratified using predictive
index for stroke risk [e.g., CHADS2 ] and for risk of bleeding [e.g., HAS-BLED] and that most patients receive either OAC or ASA.
1. Skanes AC, et al. Can J Cardiol 2012;28:125-136
Overview of NOAC clinical trials versus warfarin:
ARISTOTLE, RE-LY, ROCKET-AF
Apixaban:
ARISTOTLE trial1
Dabigatran:
RE-LY trial2
Rivaroxaban:
ROCKET-AF trial3
Summary
Randomized, double-blind, noninferiority trial
comparing apixaban 5mg BID with warfarin (target
INR 2.0-3.0); primary outcome: ischemic or
hemorrhagic stroke or systemic embolism; secondary
outcome: testing superiority with respect to primary
outcome and bleeding rates; median follow-up
duration = 1.8 years
Randomized, noninferiority trial comparing
blinded, fixed-dose dabigatran 150mg or 110mg
BID, with unblinded, dose-adjusted warfarin;
primary outcome: stroke or systemic embolism;
primary safety outcome: major bleeding; median
follow-up 2.0 years
Randomized, double-blind, noninferiority
trial comparing rivaroxaban 20mg daily
with dose-adjusted warfarin; primary
outcome: stroke or systemic embolism;
secondary outcome: major bleeding;
median follow-up 1.94 years (707 days for
ITT population).
Population
18,201 patients with AF and
at least 1 risk factor for stroke
18,113 patients with AF and a risk of stroke
14,264 patients with nonvalvular AF
at increased risk of stroke
Primary efficacy outcome
Stroke or systemic embolism in ITT population :
1.27%/yr apixaban 5mg
1.60%/yr warfarin
(HR 0.79, 95% CI [0.66-0.95] P=0.001 for noninferiority; P=0.01 for superiority)
Stroke or systemic embolism in ITT population:
1.53%/yr for dabigatran 110mg (110mg (RR
0.91; 95% CI [0.74-1.11];P<0.001 for
noninferiority;P=0.32 for superiority)
1.11%/yr for dabigatran 150mg (RR 0.66; 95% CI
[0.53-0.82];P<0.001 for superiority)
1.69%/yr for warfarin group
Stroke or systemic embolism in ITT
Population:
2.1%/yr for rivaroxaban 20mg
2.4%/yr for warfarin
(HR 0.88; 95% CI[0.75-1.03] P=0.12 for
superiority)
Primary safety outcome
Major bleeding events (ISTH criteria) in Exposed
Safety population:
2.13%/yr for apixaban group
3.09%/yr for warfarin group
(HR 0.69; 95% CI [0.60-0.80]; P<0.001)
Major bleeding events (ISTH criteria) in ITT Safety
population:
2.71%/yr for dabigatran 110mg
3.11%/yr for dabigatran 150mg
3.36%/yr for warfarin group
Dabigatran 110mg vs warfarin: RR 0.80;
95%CI[0.69-0.93]; P=0.003
Dabigatran 150mg vs warfarin: RR 0.93; 95%CI
[0.81-1.07]; P=0.31
Dabigatran 110mg vs dabigatran 150mg: RR 1.16;
; 95%CI[1.00-1.34] ; P<0.052
Major and non-major bleeding events
in ITT Safety population:
14.9% /yr for rivaroxaban 20mg
14.5%/yr for warfarin group
HR in ITT population: 1.03, 95%
CI[0.96-1.11], P=0.44
Author’s Conclusions
In patients with AF, apixaban was superior to
warfarin in preventing stroke and systemic
embolism, caused less bleeding and resulted in
lower mortality.
In patients with AF, dabigatran 110mg was
noninferior to warfarin with similar rates of
stroke and systemic embolism as warfarin,
and lower rates of hemorrhage. Dabigatran
In patients with atrial fibrilation
rivaroxaban was noninferior to warfarin
for the prevention of stroke or systemic
embolism. There was no significant
Recent Oral Anticoagulation Trials:
Stroke or Systemic Embolism
THE NEW ORAL ANTICOAGULANT AGENTS ARE CONSISTENTLY ASSOCIATED WITH A
NUMERICALLY LOWER RISK FOR STROKE OR SYSTEMIC EMBOLISM COMPARED TO WARFARIN†
P Value
Dabigatran 110 mg bid
P = 0.2943
Dabigatran 150 mg bid
P < 0.0001
Rivaroxaban 20 mg qd
P = 0.12
Apixaban 5 mg bid
P = 0.01
0.50
0.75
New Agent Better
1.00
1.25
1.50
Warfarin Better
Bid=twice daily; qd=daily
†Not
intended as cross-trial comparison
Data obtained from intention-to-treat analysis
1. Connolly SJ, et al. N Engl J Med 2009;361:1139-1151. 2. Patel MR, et al. N Engl J Med 2011;365:883-891.
3. Granger C, et al. N Engl J Med 2011;365:981-992
Recent Oral Anticoagulation Trials:
Hemorrhagic Stroke
THE NEW ORAL ANTICOAGULANTS ARE CONSISTENTLY ASSOCIATED WITH
A NUMERICALLY LOWER RISK OF HEMORRHAGIC STROKE COMPARED WITH WARFARIN†
P Value
Dabigatran 110 mg bid
P < 0.001
Dabigatran 150 mg bid
P < 0.001
Rivaroxaban 20 mg qd
P = 0.24
Apixaban 5 mg bid
P < 0.001
0.00
0.25
New Agent Better
0.50
0.75
HR (95% CI)
1.00
1.25
Warfarin Better
Bid=twice daily; qd=daily
†Not
intended as cross-trial comparison
Data obtained from intention-to-treat analysis
1. Connolly SJ, et al. N Engl J Med 2009;361:1139-1151. 2. Patel MR, et al. N Engl J Med 2011;365:883-891.
3. Granger C, et al. N Engl J Med 2011;365:981-992
Mike’s Treatment Plan / Outcome
Mike was switched from warfarin to dabigatran 150 mg BID, and discharged from the emergency department.

The rationale for this decision is that the 150mg BID dose of dabigatran has superior efficacy compared to well-controlled
warfarin in preventing ischemic stroke, as well as decreased incidence of major bleeding compared to warfarin.

Dabigatran 110mg was not chosen because this dose is reserved for elderly patients (usually over 80), and patients with
increased bleeding risks, neither of which is the case with Mike.

Rivaroxaban 20mg daily was not chosen for this patient because rivaroxaban was noninferior to warfarin for the prevention of
stroke or systemic embolism in ROCKET-AF. There was no significant between-group difference in the risk of major bleeding,
although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. With this knowledge, the advantages
are greater with dabigatran than rivaroxaban for this patient.

Apixaban 5mg BID was not chosen for this patient because although ARISTOTLE has similar profile , the treating physician
was more familiar with dabigatran because it has been on the market longer and more clinical and practical data are available to
support its use in this patient.

Of note, no head-to-head comparisons in patients at risk of stroke were made with each OAC, and therefore clinical judgment
should be applied, and review of trial data should help guide clinical decision making in the choice of OACs.
1. Granger C, et al. N Engl J Med 2011;365:981-992. 2. Connolly SJ, et al. N Engl J Med 2009;361:1139-1151. 3. Patel MR, et al. N Engl J Med 2011;365:883-891.
Early Risk of Stroke after Discharge from
the Emergency Department among Patients with
a First-ever TIA
CUMULATIVE %
OF PATIENTS
READMITTED
WITH STROKE
10
8
6
4
2
0
0
20
40
1. Gladstone D et al. CMAJ. 2004 Mar 30;170(7):1099-104
60
80
100
DAYS AFTER TIA
GI Bleeding Post-treatment
 2 weeks later, Mike returns to the emergency department
with moderate-intensity GI bleeding.
 Last dose of dabigatran was 4 hours before admission.
 BP: 118/75 mmHg
 Pulse: 82 bpm
 CrCl: 66 mL/min
Anticoagulation Management During
GI Bleeding
 The following steps could be undertaken to assess and
manage the patient:







Investigate the source of bleeding
Assess renal function
Assess coagulation
Assess prior bleed history
Assess concomitant medications
Assess timing of last dose of dabigatran
Assess current management of ASA
Management of Bleeding
 In patients treated with dabigatran:

Treatment should be individualized according to the severity
and location of the hemorrhage

As protein binding is low, dabigatran can by dialysed,
although there is limited clinical experience in using dialysis
in this setting

Discontinue dabigatran, do not reduce the dose

Investigate the source of the bleeding

Dabigatran has a short half-life (12-14 hours)
van Ryn J et al. Thromb Haemost 2010;103:1116-1127. Canadian Pradaxa Product Monograph Boehringer Ingelheim (Canada) Ltd. Dec 24, 2012
Bytzer P et al. Clin Gastroenterol Hepatol 2013;11(3):246-52.
Management of Bleeding
 Maintain adequate diuresis before initiation of standard
treatment:



Surgical hemostasis
Blood volume replacement (e.g., whole blood, FFP)
Application of factor concentrates (some preclinical evidence,
limited clinical evidence available):
• Prothrombin complex concentrates
(PCC; e.g., non-activated or activated)
• Recombinant Factor VIIa
• Use of platelet concentrates may be considered where
thrombocytopenia is present or long-acting antiplatelet drugs
have been used
van Ryn J et al. Thromb Haemost 2010;103:1116-1127. Canadian Pradaxa Product Monograph Boehringer Ingelheim (Canada) Ltd. Dec 24, 2012
CONTRAINDICATIONS with each NOAC
Apixaban
Dabigatran
Rivaroxaban
Concomitant systemic treatment with strong
inhibitors of both CYP 3A4 and P-glycoprotein (Pgp) such as azole-antimycotics, e.g., ketoconazole,
itraconazole, voriconazole, or posaconazole, and
HIV protease inhibitors, e.g., ritonavir;
Concomitant treatment with any other
anticoagulants
Clinically significant active bleeding
Recent lesions at risk of significant bleeding (eg
cerebral infarction)
Patients with severe renal impairment (CrCl< 30
mL/min)
Concomitant treatment with strong P-glycoprotein
(P-gp) inhibitors, i.e. oral ketoconazole
Concomitant use with any other anticoagulants
Prosthetic valve anticoagulation
Hemorrhagic manifestations
Lesions at risk of significant bleeding (eg cerebral
infarction) within six months
Concomitant systemic treatment with strong
inhibitors of both CYP 3A4 and P-glycoprotein(Pgp), azole antimycotics, such as ketoconazole,
itraconazole, , and HIV protease inhibitors, e.g.,
ritonavir; significant hepatic disease, pregnancy,
breastfeeding
Concomitant treatment with any other
anticoagulants
Recent lesions at risk of significant bleeding (eg
cerebral infarction)
*The list of contraindications includes the most prominent ones is included in the table above, but is not exhaustive. For more information, refer
to respective Product Monographs
Canadian Eliquis Product Monograph Pfizer Canada Inc. / Bristol-Myers Squibb Canada. Nov 27, 2012.
Canadian Pradaxa Product Monograph Boehringer Ingelheim (Canada) Ltd. Dec 24, 2012.
Canadian Xarelto Product monograph Bayer Inc. (Canada) June 5, 2013.
Dabigatran Etexilate-specific Care
 Assess coagulation



Do not use INR testing
Use aPTT and/or diluted TT (HEMOCLOT®) every 3 hours
Use test results to guide treatment decisions
For patients on 150 mg BID at trough
(10–16 hours after the previous dose):
aPTT ratio >2-3 fold
(aPTT prolongation ~80 seconds),
may indicate increased
risk of bleeding
HEMOCLOT® TT
measure of >65 seconds
(>200 ng/mL dabigatran plasma
concentration) is associated with a
higher risk of bleeding
aPTT = activated partial thromboplastin time; BID = twice daily; INR = international normalized ratio;
TT = thrombin time; ULN = upper limit of normal
Weitz et al Circulation 2012.
Management of Moderate-Severe Bleeding
Moderate-severe
bleeding






Stop
Dabigatran
Identify source of bleeding
Verify time of the last dabigatran dose – if within 0-4 hours, consider oral activated charcoal
Measure anticoagulant activity (aPTT and/or Hemoclot, if available)
Measure creatinine, calculate creatinine clearance and estimate dabigatran half-life
Local/surgical hemostasis as appropriate
General measures: Volume replacement/blood product transfusions
Bleeding Stops
Bleeding continues – further management is required
ICH or
life-threatening
bleeding
*Consider procoagulants: Start with PCC (40 IU/kg)
If bleeding continues, give FEIBA (50 IU/kg)
If bleeding continues, give rFVIIa (90 μg/kg)
Administer FEIBA (50 IU/kg)*
- If unavailable, give PCC
(40 IU/kg or rFVIIa (90 μg/kg)
*If bleeding cannot be managed (hemodynamically
unstable, renal impairment), consider hemodialysis
(toxin protocol, heparin free) for 6 to 8 hours or charcoal
filtration
- Monitor aPTT and/or Hemoclot every 3 hours
In general, it is preferable to wait at least 30 min to assess the effect of each therapy before initiating next therapy.
FEIBA is a freeze dried sterile human plasma fraction that shortens the activated partial thromboplastin time (APTT)
Weitz et al. Periprocedural Management and Approach to Bleeding in Patients Taking Dabigatran. Circulation 2012;126:2428-32.
About Bleeding with Dabigatran*
 Patients with major bleeding on dabigatran are older, have lower CrCl, and greater
use of ASA and NSAIDs.
 Major bleeds in the dabigatran groups were more frequently treated with blood
transfusions than those on warfarin but less frequently with plasma.
 Length of stay in ICU is shorter with dabigatran treatment than with comparator.
 A Kaplan–Meier analysis indicated a reduced risk for death with dabigatran
(combined 150mg and 110mg BID) vs warfarin during 30 days from the bleeding
(P=0.044).
 Adjusted analysis demonstrates mortality benefit for dabigatran in RE-LY®
 Despite the unavailability of a specific antidote against dabigatran, the overall
resources required to manage bleeding are not greater.

The prognosis (survival) after a major bleed on dabigatran appeared, despite lack
of a specific antidote, better than after a warfarin-associated bleed.
_____________________________________________________________________
*Data based on RELY study subanalysis and pooled analysis of dabigatran trials with duration > 6 mo
Majeed A. et al. Management and Outcomes of Major Bleeding on Dabigatran or Warfarin,
American Society of Hematology Conference , Atlanta, GA, Dec 2012
About Bleeding with Dabigatran (cond’t)
 Clinical implications:

Dabigatran’s safety profile is more favourable than that of
warfarin, even in the presence of effective reversal agents for
warfarin.

The management of severe bleeding on dabigatran can be
further improved by access to a specific antidote, which is in
development.
Majeed A. et al. Management and Outcomes of Major Bleeding on Dabigatran or Warfarin,
American Society of Hematology Conference , Atlanta, GA, Dec 2012
About Bleeding with Dabigatran:
Periprocedural Bleeding Subanalysis
 This subanalysis of RELY followed the bleeding risk from 7 days before till 30




days after an invasive procedure in patients receiving dabigatran or warfarin in
a blinded fashion
Compared with warfarin, both doses of dabigatran associated with similar
rates of:
 Peri-procedural* bleeding (including major and fatal bleeding)
 Thrombotic complications
There is low incidence of thromboembolic events across all treatment groups.
There is a similar risk of bleeding within each surgery type; no significant
interaction between surgery type and treatment.
There is a significantly lower rate of bleeding with dabigatran (both doses) for
patients undergoing surgery within 48 hours of anticoagulation interruption.
 For patients who underwent procedure within 48 hours of stopping
anticoagulation:
 Bleeding risk was lower in the dabigatran vs warfarin
(DB 110mg = 17.8% vs warfarin = 21.6%)
1. Healey JS et al. Circulation 2012;126:343-348. 2. Connolly SJ, et al. N Engl J Med 2009;361:1139-1151.
Concerns About Prescribing Dabigatran
 Recent post-marketing reports of bleeding with dabigatran, when used for




stroke prevention in patients with AF, have the potential to be misinterpreted
and provide an inaccurate impression of the drug’s safety.
Bleeding with dabigatran must be interpreted in the context of its benefits
(see next slide).
Both dabigatran and warfarin are likely to be associated with higher rates of
bleeding in clinical practice than those observed in randomized controlled
trials such as RE-LY, because patients included in trials tend to be healthier
than in the general community.
However, differences in bleeding rates (ICH), between RE-LY and the general
community are likely to be even greater for warfarin than dabigatran because
both the INR and blood pressure control (the single most important predictor
of ICH during warfarin therapy) were much better in RE-LY than in average
clinical practice.
Those with access to databases from provincial, national or insurance
registries are encouraged to report the relative use of various antithrombotic
therapies for AF and the rates of thrombotic and bleeding events.
Eikelboom JW, Quinlan DJ, Connolly SJ, Hart RG, Yusuf S. Dabigatran efficacy–safety assessment for stroke prevention in patients with atrial
fibrillation. J Thromb Haemost 2012; 10: 966–8.
Reports of Bleeding with Dabigatran Need
to be Interpreted in Context
Dabigatran (230)
Warfarin (329)
Aspirin (200)
No treatment (153)
FATAL BLEEDING
Dabigatran (300)
Warfarin (618)
Aspirin (279)
No treatment (136)
INTRACRANIAL
BLEEDING
Dabigatran (1010)
Warfarin (1540)
TOTAL STROKES
Aspirin (3450)
No treatment (5998)
Dabigatran (3640)
Warfarin (4035)
ALL-CAUSE MORTALITY
Aspirin (6172)
No treatment (6664)
0
1000
2000
3000
4000
5000
6000
7000
NO. EVENTS PER 100,000 PATIENTS WITH AF TREATED/OBSERVED OVER 1 YEAR
Eikelboom JW, Quinlan DJ, Connolly SJ, Hart RG, Yusuf S. Dabigatran efficacy–safety assessment for stroke prevention in patients with atrial
fibrillation. J Thromb Haemost 2012; 10: 966–8.
Poor Prognosis in Warfarin-Associated
Intracranial Hemorrhage Despite
Anticoagulant Reversal
Dowlatshahi D, et al. Stroke 2012. DOI: 10.1161/STROKEAHA.112.652065
Hematoma Growth
Significant hematoma growth despite INR
correction with PCC.
This patient was treated with 1000 U of PCC
and 10 mg vitamin K 98 minutes after baseline
CT scan.
Repeat INR was 1.3, 42 minutes after PCC
treatment and 1.2 the next day.
INR = international normalized ratio;
PCC = prothrombin complex concentrate
Dowlatshahi D, et al. 2012. DOI: 10.1161/STROKEAHA.112.652065
What-if Scenarios
 Mike wants to know when he can travel next.
 What if his Doppler shows:


< 50% carotid artery stenosis?
50-69% carotid artery stenosis?
 What if Mike’s CT report reads:

Small area of hypodensity in the right centrum semiovale consistent
with infarction
 What if Mike experienced a TIA more recently, e.g., this morning?


What investigations should be conducted; what are any differences
between these investigations and those done if the TIA was
experienced 3 weeks ago?
ECG, Blood work (including INR), renal function and lipid profile.
 Brain/neurovascular imaging to exclude a bleed or a large infarct
Recovery after GI Bleeding
 What would be your anticoagulation strategy for this patient?
 When would you consider re-starting anticoagulant?
 What dose would you suggest?
 Would you provide any additional guidance
What is the rationale for your choice?
Recovery after GI Bleeding
 How would your guidance change if:

The bleeding had been life-threatening?

The patient was at high risk of stroke?

This was not the first GI bleed experienced by the patient?

The patient had experienced a previous TIA/stroke which had
precipitated their move to dabigatran treatment?
• Would input from the treating neurologist also be useful at this stage?
 A coronary artery stent was fitted 3 months previously?
TIA = transient ischaemic attack
Key Points
 The primary goal of OAC treatment is to reduce the risk of
ischaemic stroke while minimizing the risk for intracranial and
other bleeding
 It is important that patients and physicians be vigilant for the
signs and symptoms of GI bleeding
 A number of different strategies are available for managing
patients with bleeding

Largely depending on bleeding severity, degree of anticoagulation,
and patient renal function

Vitamin K should not be used, as this will not reverse the action
of dabigatran
 Dabigatran has a short half-life. Bleed management options are
available.
Connolly NEJM 2010;363:18 van Ryn J et al. Thromb Haemost 2010;103:1116–27 Skanes et al. Focused 2012 Update of the Canadian Cardiovascular Society
Atrial Fibrillation Guidelines: Recommendations for Stroke Prevention and Rate/Rhythm Control. Canadian Journal of Cardiology 28 (2012) 125–136 76