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ACS and Thrombosis in the Emergency Setting. ER Direct Case: Management of Atrial Fibrillation and Post-Treatment Bleeding in Patient with Prior TIA. Faculty/Presenter Disclosure. Faculty : Andre Douen, MD,PhD,FRCPC,FAHA Relationships with commercial interests:

I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
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faculty presenter disclosure
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

disclosure of commercial support
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
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
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.

new oral anticoagulants
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)

patient presentation
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
Medical History

Previous conditions:

  • Mike was diagnosed with AF3 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.


  • Mike is married and lives with his 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
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) -

management options
Management Options
  • Options for management include:
    • Remain on warfarin with more frequent INR determinations OR
    • Switch to one of the new OAC agents
  • 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
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:
  • Rivaroxaban: Contraindicated with recent cerebral infarction.
chads 2 score simple prediction tool for assessing stroke risk
CHADS2 Score(Simple Prediction Tool for Assessing Stroke Risk)

1 POINT forCongestive Heart Failure

1 POINT for Hypertension

1POINT forAge ≥ 75 years

1 POINT forDiabetes Mellitus

2 POINTS forPrior Stroke or TIA

Gage BF, et al. JAMA. 2001;285:2864-2870.

cha 2 ds 2 vasc score novel stroke risk stratification tool complements chads 2
CHA2DS2-VASc ScoreNovel Stroke Risk Stratification Tool, Complements CHADS2

1POINT for Congestive Heart Failure/LV Dysfunction

1POINT for Hypertension

2POINTS for Age ≥ 75 years

1POINT for Diabetes Mellitus

2POINTS for Prior Stroke or TIA1 or TE2

1POINT for Vascular Disease3

1POINT for Age 65-74 years

1POINT for Sex category (female gender)

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:d1243. 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
HAS-BLED Bleeding Score(Simple Tool for Assessing Bleeding Risk)

1. Pisters R, et al. Chest 2010; 138(5):1093–1100


HAS-BLED Bleeding Score(Simple Tool for Assessing Risk of Major Bleeding within1 Year in Patients with AF Enrolled in the Euro Heart Survey)

1. Pisters R, et al. Chest 2010; 138(5):1093–1100

ccs 2012 update to af guidelines
CCS 2012 Update to AF Guidelines

Assess Thromboembolic Risk (CHADS2)

OAC = Oral anticoagulant

ASA = Aspirin

CHADS2 ≥ 2

CHADS2 = 0

CHADS2 = 1






No anti-thrombotic

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
Overview of NOAC clinical trials versus warfarin: ARISTOTLE, RE-LY, ROCKET-AF
  • 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.
recent oral anticoagulation trials stroke or systemic embolism
Recent Oral Anticoagulation Trials:Stroke or Systemic Embolism


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






New Agent Better

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
Recent Oral Anticoagulation Trials:Hemorrhagic Stroke


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







New Agent Better

Warfarin Better

HR (95% CI)

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’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 fromthe Emergency Department among Patients with a First-ever TIA















1. Gladstone D et al. CMAJ. 2004 Mar 30;170(7):1099-104

gi bleeding post treatment
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
Anticoagulation Management DuringGI 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
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. ThrombHaemost2010;103:1116-1127. Canadian Pradaxa Product Monograph Boehringer Ingelheim (Canada) Ltd. Dec 24, 2012

Bytzer P et al. ClinGastroenterolHepatol 2013;11(3):246-52.

management of bleeding1
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. ThrombHaemost2010;103:1116-1127.Canadian Pradaxa Product Monograph Boehringer Ingelheim (Canada) Ltd. Dec 24, 2012

contraindications with each noac

*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 BoehringerIngelheim (Canada) Ltd. Dec 24, 2012.

Canadian Xarelto Product monograph Bayer Inc. (Canada) June 5, 2013.

dabigatran etexilate specific care
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 increasedrisk of bleeding

HEMOCLOT® TTmeasure 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
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 orlife-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
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) vswarfarin 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
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
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
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 ThrombHaemost2012; 10: 966–8.

reports of bleeding with dabigatran need to be interpreted in context
Reports of Bleeding with Dabigatran Need to be Interpreted in Context

Dabigatran (230)

Warfarin (329)


Aspirin (200)

No treatment (153)

Dabigatran (300)

Warfarin (618)


Aspirin (279)

No treatment (136)

Dabigatran (1010)

Warfarin (1540)


Aspirin (3450)

No treatment (5998)

Dabigatran (3640)

Warfarin (4035)


Aspirin (6172)

No treatment (6664)










Eikelboom JW, Quinlan DJ, Connolly SJ, Hart RG, Yusuf S. Dabigatran efficacy–safety assessment for stroke prevention in patients with atrial fibrillation. J ThrombHaemost2012; 10: 966–8.

poor prognosis in warfarin associated intracranial hemorrhage despite anticoagulant reversal
Dowlatshahi D, et al. Stroke 2012. DOI: 10.1161/STROKEAHA.112.652065Poor Prognosis in Warfarin-Associated Intracranial Hemorrhage Despite Anticoagulant Reversal
hematoma growth
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
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
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 bleeding1
TIA = transient ischaemic attackRecovery 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?
key points
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 actionof 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