1. ACS and Thrombosis in the Emergency Setting
ER Direct Case: Management of Atrial Fibrillation and Post-Treatment Bleeding in Patient with Prior TIA

2. AF, Stroke and New Oral Anticoagulants
Atrial fibrillation (AF) affects over 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.
New Oral Anticoagulants include:
Dabigatran: Indications: 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. 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.
Rivaroxaban: Indications: 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: Indications: Prevention of VTE in elective hip or knee replacement (2.5mg BID), and prevention of stroke and systemic embolism in AF (5mg BID).
Generally, 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 atrial fibrillation is stroke. Individuals with atrial fibrillation have a risk of stroke that is 3 to 5 times greater than those without AF.
Heart and Stroke Foundation

3. Stroke in AF patients
Atrial fibrillation (AF) affects over 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.
Generally, 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 atrial fibrillation is stroke. Individuals with atrial fibrillation have a risk of stroke that is 3 to 5 times greater than those without AF.
Heart and Stroke Foundation

4. 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.”

5. Medical History Previous conditions: Lifestyle:
Mike was diagnosed with AF 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.
Lifestyle:
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 1 glass of wine or beer/day.
This increases to 2-3 glasses of wine or beer/day when he is travelling (about once/month).

6. Physical Examination and Labs
Height 5’11’’ (180 cm), weight 187 lbs (85 kg), BMI is
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) -

7. 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
STANDARD DOSE
LOWER DOSE
Apixaban
5 mg BID
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
Dabigatran
150 mg BID
110 mg BID for patients ≥80 years or patients ≥75 years with a risk factor for bleeding
Rivaroxaban
20 mg QD
15 mg QD in patients with CrCl mL/min
Lindsay MP, Gubitz G, Baylay M, Phillips S (editors), on behalf of the Canadian Stroke Best Practices and Standards Working Group. Canadian Best Practice Recommendations for Stroke Care. Fourth Edition. Chapter 2, Stroke Prevention. Update September p.36-38
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)

8. 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.

9. 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)
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
The CHADS2 index is a clinical prediction scheme that can be used to identify AF patients who are at high risk for stroke and require anticoagulation. Physicians and patients should use CHADS2 to make decisions about antithrombotic therapy based on patient-specific risk of stroke.
The CHADS2 index is calculated by assigning 1 point each for the presence of congestive heart failure, history of hypertension, age ≥ 75 years, diabetes mellitus and by assigning 2 points for a history of transient ischemic attack or ischemic stroke.
This index was validated in a prospective cohort study including 1733 patients who were identified using the national registry of AF (registry of US Medicare beneficiaries who had AF). Patients were followed for 1.2 years (or a total of 2121 patient-years) during the study.
The stroke rate was lowest among those who had a CHADS2 score of 0 and the stroke rate increased by a factor of 1.5 (95% CI, ) for each 1-point increase in the CHADS2 score (P<0.001).
The CHADS2 index provides an accurate tool for assessing stroke risk on an individual basis, and helping physicians and patients determine appropriate treatment modalities.
Reference
Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285:
Gage BF, et al. JAMA. 2001;285:

10. 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 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
0.78 (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
CHA2DS2-VASc is a novel stroke risk stratification scheme, developed to complement CHADS2 by considering additional risk modifiers such as, female gender, slightly younger age range (65-74 years) and vascular disease. This provides some improvement in predictive value for thromboembolism over the CHADS2 risk stratification score, especially for patients categorized as low and intermediate risk by CHADS2. This may be clinically important as many patients at low risk according to CHADS2 may not be at “truly low risk” and treatment guidelines are not conclusive for those at intermediate risk
The CHA2DS2-VASc score is calculated using a point system in which 2 points are assigned for a history of stroke or TIA, or age ≥75; and 1 point each is assigned for age 65–74 years, a history of hypertension, diabetes, recent cardiac failure, vascular disease (myocardial infarction, complex aortic plaque, and peripheral artery disease), and female gender
The CHA2DS2-VASc scheme may improve the approach to stroke risk stratification in patients with atrial fibrillation
References
Lip GYH, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach. Chest 2010;137(2):
Olesen JB, et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ 2011;342:d124.
Guidelines for the management of atrial fibrillation: Task Force for the management of atrial fibrillation of the European Society of Cardiology. Eur Heart J 2010;31:2369–2429.
1TIA = Transient ischemic attack; 2TE = Thromboembolism; 3Prior myocardial infarction, peripheral artery disease, aortic plaque
1. Lip GY et al. Chest 2010;137: Olesen JB, et al. BMJ 2011;342:d Task Force or the Management of Atrial Fibrillation of the ESC. Eur Heart J 2010;31:

11. 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 B
Bleeding L
Labile INRs E
Elderly D
Drugs or alcohol (1 point each)
*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).
Although warfarin and other anticoagulants can prevent ischemic events, they can cause hemorrhage. Quantifying the rate of hemorrhage is important for determining the risks and net benefits of prescribing antithrombotic therapy. Fear of hemorrhage is a major reason why antithrombotic therapy has been underused in patients with atrial fibrillation. The efficacy of any anticoagulant therapy for the prevention of stroke must be balanced against the risk of major hemorrhage, particularly cerebral hemorrhage, which is often fatal
It is recognized that several risk factors predisposing to bleeding are also risk factors for stroke. HAS-BLED is a novel bleeding risk score that provides an easy, practical tool to assess the individual bleeding risk of patients with AF; it is derived from the Euro Heart Survey on AF. The use of this simple score may potentially support clinical decision making regarding antithrombotic therapy for stroke prevention. The Canadian Cardiovascular Society recommends that HAS-BLED be used to determine bleeding risk in patients with AF who may be candidates for anticoagulant therapy
HAS-BLED is based on the following clinical characteristics considered important for determining bleeding risk: 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 antiinflammatory drugs; one point for drugs plus one point for alcohol excess, maximum two points). Bleeding rate is determined based upon the risk score calculated
Reference
Pisters R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation. Chest 2010;138(5):
1. Pisters R, et al. Chest 2010; 138(5):1093–1100

12. 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)
1.13 1
1.02 2
1.88 3
3.74 4
8.70 5
12.50
The risk of major bleeding within one year (annual bleeding rate) increased with the addition of each risk factor
It is recognized that several risk factors predisposing to bleeding are also risk factors for stroke. HAS-BLED is a novel bleeding risk score that provides an easy, practical tool to assess the individual bleeding risk of patients with AF; it is derived from the Euro Heart Survey on AF. The use of this simple score may potentially support clinical decision making regarding antithrombotic therapy for stroke prevention. The Canadian Cardiovascular Society recommends that HAS-BLED be used to determine bleeding risk in patients with AF who may be candidates for anticoagulant therapy
Reference
Pisters R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation. Chest 2010;138(5):
1. Pisters R, et al. Chest 2010; 138(5):1093–1100

13. 1pt for hypertension, 1pt for diabetes, 2pts for prior TIA
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 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

14. CCS 2012 Update to AF Guidelines
CHADS2 = 0
CHADS2 = 1
CHADS2 ≥ 2
No anti-thrombotic
No additional risk factors for stroke
INCREASING STROKE RISK
ASA
OAC*
OAC
OAC = Oral anticoagulant
ASA = Aspirin
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
Assess Thromboembolic Risk (CHADS2)
The Canadian Cardiovascular Society after updating the guidelines in 2010 for Atrial Fibrillation decided that they would have future updates in a more timely manner as new evidence became available that would address important clinical advances. In 2011, three pivotal trials, ROCKET AF, ARISTOTLE and PALLAS on new medications (rivaroxaban, apixaban and dronedarone respectively) were published. In addition, new data on prediction tools for AF related stroke and bleeding risk, stroke risk in paroxysmal AF patients, risk/benefit considerations in relation to oral anticoagulation in patients with chronic kidney disease, risk/benefit considerations in the use of antiplatelet agents alone and in combination with each other or with anticoagulants in AF patients also became available.
The recommendations for antithrombotic agents are as follows:
All patients with atrial fibrillation (paroxysmal, persistent, or permanent) should be stratified using a predictive index for stroke (e.g. CHADS2) and for the risk of bleeding (e.g. HAS-BLED) and most patients should receive an oral anticoagulant (OAC) or ASA. When an oral anticoagulant is indicated most patients should receive either dabigatran, rivaroxaban or apixaban (once approved) in preference to warfarin.
Patients at high risk of stroke (CHADS2≥2) should receive OAC.
Most patients at intermediate risk of stroke (CHADS2=1) should receive OAC therapy. Based on individual risk/benefit considerations, ASA is a reasonable alternative for some patients.
Patients at low risk of stroke (CHADS2=0) should have additional risk factors for stroke considered (including age years, female sex, and presence of vascular disease). OAC therapy is suggested for patients at highest risk within this category (age >65 years, or the combination of female sex and vascular disease); ASA ( mg/day) for patients at lower risk within this category(female sex or vascular disease); no antithrombotic therapy for those patients at lowest risk in this category (no additional risk factors).
References
Cairns JA, et al. Canadian Cardiovascular Society Atrial Fibrillation Guidelines 2010: Prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter. Can J Cardiol 2011;27:74-90.
Skanes et al. Focussed 2012 update to the Canadian Cardiovascular Society atrial fibrillation guidelines: Recommendations for stroke prevention and rate/rhythm control. Can J Cardiol 2012; 28:
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:

15. 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 ); 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 [ ] P=0.001 for non-inferiority; P=0.01 for superiority)
Stroke or systemic embolism in ITT population:
1.53%/yr for dabigatran 110mg (110mg (RR 0.91; 95% CI [ ];P<0.001 for noninferiority;P=0.32 for superiority)
1.11%/yr for dabigatran 150mg (RR 0.66; 95% CI [ ];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[ ] 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 [ ]; 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[ ]; P=0.003
Dabigatran 150mg vs warfarin: RR 0.93; 95%CI [ ]; P=0.31
Dabigatran 110mg vs dabigatran 150mg: RR 1.16; ; 95%CI[ ] ; 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[ ], 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 150mg had lower rates of stroke (both hemorrhagic and ischemic) and SE compared to warfarin, and similar rates of hemorrhage.
In patients with atrial fibrilation rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and major bleeding occured less frequently in the rivaroxiban group.
Safety population definitions:
ARISTOTLE: Pt who rec’d at least one dose of study drug followed from time of fist dose until 2 days after last dose was received.
RE-LY: ITT
ROCKET AF: Pt who rec’d at least one dose of study drug followed from time of fist dose until 2 days after discontinuation from study drug.
Granger C, et al. N Engl J Med 2011;365: Connolly SJ, et al. N Engl J Med 2009;361: Patel MR, et al. N Engl J Med 2011;365:

16. 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†
Bid=twice daily; qd=daily
Dabigatran 110 mg bid
Dabigatran 150 mg bid
Rivaroxaban 20 mg qd
Apixaban 5 mg bid
P =
P <
P = 0.12
P = 0.01
P Value
New Agent Better
Warfarin Better
0.50
0.75
1.00
1.50
1.25
This data is the primary outcome parameter taken from the pivotal outcome trials for each of the newer anticoagulants compared to warfarin. The trend for each of the agents (significant for some) is clearly in the direction of reduced stroke or systemic embolism for the newer agents vs warfarin.
For dabigatran the RE-LY trial randomized 18,113 patients with atrial fibrillation in a blinded manner to dabigatran 110 mg bid, 150 mg bid or in an unblinded fashion to warfarin. The median duration of follow up was 2 years.
For rivaroxaban 14,264 patients with non valvular atrial fibrillation in the ROCKET AF trial were randomized to 20 mg of rivaroxaban od or to dose adjusted warfarin. The median duration of follow up was 707 days.
For apixaban, 18,201 patients with atrial fibrillation in the ARISTOTLE trial were randomized to either 5 mg bid of apixaban or to dose adjusted warfarin. The median duration of follow up was 1.8 years.
References
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):
Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):
†Not intended as cross-trial comparison
Data obtained from intention-to-treat analysis
1. Connolly SJ, et al. N Engl J Med 2009;361: Patel MR, et al. N Engl J Med 2011;365: Granger C, et al. N Engl J Med 2011;365:

17. Recent Oral Anticoagulation Trials: Hemorrhagic Stroke
THE NEW ORAL ANTICOAGULANTS ARE CONSISTENTLY ASSOCIATED WITH A NUMERICALLY LOWER RISK OF HEMORRHAGIC STROKE COMPARED WITH WARFARIN†
Dabigatran 110 mg bid
Dabigatran 150 mg bid
Rivaroxaban 20 mg qd
Apixaban 5 mg bid
P < 0.001
P = 0.24
P Value
Bid=twice daily; qd=daily
New Agent Better
Warfarin Better
0.00
0.25
0.50
1.00
0.75
1.25
HR (95% CI)
Care must be exercised when comparing across trials for a single secondary outcome parameter since the definitions of the event may differ between trials.
In the dabigatran trial stroke was defined as “the sudden onset of focal neurologic deficit in a location consistent with the territory of a major cerebral artery and categorized as ischemic, hemorrhagic or unspecified. Hemorrhagic transformation of ischemic stroke was not considered to be a hemorrhagic stroke.” Hemorrhagic stroke occurred in 14 patients on 110 mg bid of dabigatran , 12 patients on 150 mg and 45 patients on warfarin.
In the rivaroxaban study stroke was defined as: “a sudden, focal neurological deficit of presumed cerebrovascular cause that was neither reversible within 24 hours nor due to any other readily identifiable cause, such as tumour, trauma or seizure.” Brain imaging was used to distinguish between ischemic and hemorrhagic stroke. The number of events of hemorrhagic stroke was 33 on rivaroxaban and 57 on warfarin.
In the apixaban trial stroke was defined as: “a focal neurologic deficit, from a nontraumatic cause, lasting at least 24 hours and was categorized as ischemic (with or without hemorrhagic transformation) hemorrhagic or of uncertain type (in the case of patients that did not undergo brain imaging or in whom an autopsy was not performed).” Hemorrhagic stroke occurred in 40 patients in the apixaban group and 78 patients in the warfarin group.
References
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):
Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):
Hankey GJ, Patel MR, Stevens SR, Becker RC, Breithardt G, Carolei A, Diener HC, Donnan GA, Halperin JL, Mahaffey KW, Mas JL, Massaro A, Norrving B, Nessel CC, Paolini JF, Roine RO, Singer DE, Wong L, Califf RM, Fox KA, Hacke W; ROCKET AF Steering Committee Investigators. Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurol. 2012;11(4):
†Not intended as cross-trial comparison
Data obtained from intention-to-treat analysis
1. Connolly SJ, et al. N Engl J Med 2009;361: Patel MR, et al. N Engl J Med 2011;365: Granger C, et al. N Engl J Med 2011;365:

18. 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 showed favorable results for use in patients with risk of stroke or systemic embolism, this is a relatively newer drug on the market and less 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: Connolly SJ, et al. N Engl J Med 2009;361: Patel MR, et al. N Engl J Med 2011;365:

19. Early Risk of Stroke after Discharge from the Emergency Department among Patients with a First-ever TIA
CUMULATIVE % OF PATIENTS READMITTED WITH STROKE 2 4 6 8 10 20 40 60 80
100
DAYS AFTER TIA
The analysis for this study was based on the Ontario Stroke Registry established by the Heart and Stroke Foundation of Ontario. The registry prospectively identified consecutive patients with cerebrovascular disease that presented to the emergency department of 4 acute tertiary care centres from May to December Three quarters of the TIA patients were discharged from the emergency department. After discharge the 30 day stroke risk was 5% (13/265) overall and 8% (13/167) for those with a first ever TIA.
Half of the patients that had a stroke within 90 days after discharge did so within the first 2 days.
The authors suggest that “Patients in whom TIA is diagnosed in the emergency department have high immediate and short term risks of stroke. However, their condition is underinvestigated and undertreated compared with stroke: many do not receive the minimum recommended diagnostic tests within 30 days.”
Reference
Gladstone DJ, Kapral MK, Fang J, Laupacis A, Tu JV. Management and outcomes of transient ischemic attacks in Ontario. CMAJ. 2004;170(7):
1. Gladstone D et al. CMAJ Mar 30;170(7):

20. 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

21. 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

22. 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)
As with all anticoagulants, dabigatran should be used with caution in circumstances associated with an increased risk of bleeding. Bleeding can occur at any site during therapy with dabigatran. The possibility of a hemorrhage should be considered in evaluating the condition of any anticoagulated patient. An unexplained fall in hemoglobin and/or hematocrit or blood pressure should lead to a search for a bleeding site. Patients at high risk of bleeding should not be prescribed dabigatran.
Dose reduction of dabigatran does not appear to improve GI-related bleeding. (Bytzer P et al. Analysis of upper gastrointestinal adverse events among patients given dabigatran in the RE-LY trial. Clin Gastroenterol Hepatol Mar;11(3): e1-5. doi: /j.cgh )
Should severe bleeding occur, treatment with dabigatran must be discontinued and the source of bleeding investigated promptly.
Close clinical surveillance (looking for signs of bleeding or anaemia) is recommended throughout the treatment period, especially if risk factors are combined.
van Ryn J et al. Thromb Haemost 2010;103: Canadian Pradaxa Product Monograph Boehringer Ingelheim (Canada) Ltd. Dec 24, 2012
Bytzer P et al. Clin Gastroenterol Hepatol 2013;11(3):

23. 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
Canadian Pradaxa Product Monograph Boehringer Ingelheim (Canada) Ltd. Dec 24, 2012
van Ryn J et al. Thromb Haemost 2010;103: Canadian Pradaxa Product Monograph Boehringer Ingelheim (Canada) Ltd. Dec 24, 2012

24. CONTRAINDICATIONS with each NOAC
Apixaban
Dabigatran
Rivaroxaban
Concomitant systemic treatment with strong inhibitors of both CYP 3A4 and P-glycoprotein (P-gp) 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(P-gp), azole antimycotics, such as ketoconazole, itraconazole, , and HIV protease inhibitors, e.g., ritonavir; significant hepatic disease, pregnancy, breastfeeding
Canadian Pradaxa Product Monograph Boehringer Ingelheim (Canada) Ltd. Dec 24, 2012
*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.

25. 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.

26. Management of Moderate-Severe Bleeding
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
Administer FEIBA (50 IU/kg)* - If unavailable, give PCC
(40 IU/kg or rFVIIa (90 μg/kg)
Moderate-severe bleeding
Stop Dabigatran
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)
*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.
Weitz et al. Periprocedural Management and Approach to Bleeding in Patients Taking Dabigatran. Circulation 2012;126:

27. Management of Bleeding
Mild bleeding
Patient with bleeding on dabigatran therapy
Life-threatening bleeding
Moderate-Severe bleeding
Delay next dose or discontinue treatment as appropriate
Discontinue dabigatran
Consideration of rFVIIa or PCC*
Charcoal filtration*
Symptomatic treatment
Mechanical compression
Surgical intervention
Fluid replacement and hemodynamic support
Blood product transfusion
Oral charcoal application* (if dabigatran taken < 2 hrs prior)
Hemodialysis
* Based on limited non-clinical data only, there is no experience in volunteers or patients rFVIIa: recombinant activated factor VII; PCC: prothrombin complex concentrates
van Ryn J et al. Thromb Haemost 2010;103:

28. 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

29. 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

30. 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: Connolly SJ, et al. N Engl J Med 2009;361:

31. 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.

32. Reports of Bleeding with Dabigatran Need to be Interpreted in Context
1000
2000
3000
4000
5000
6000
7000
FATAL BLEEDING
INTRACRANIAL BLEEDING
TOTAL STROKES
ALL-CAUSE MORTALITY
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)
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.

33. 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

34. 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?

35. 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

36. 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