ER Direct Case: Management of Atrial Fibrillation and Post-Treatment

Bleeding in Patient with Prior TIA

ACS and Thrombosis in the Emergency Setting

AF, Stroke and New Oral Anticoagulants

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.

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).

http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.5052135/k.15A/Atrial_fibrillation.htm?utm_campaign=offline&utm_source=bepulseaware&utm_medium=vanit

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=bepulseaware&utm_medium=vanithttp://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3483991/

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: 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).

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 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 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 ScoreNovel Stroke Risk Stratification Tool, Complements CHADS2

1 POINT for Congestive Heart Failure/LV Dysfunction1 POINT for Hypertension2 POINTS for Age ≥ 75 years1 POINT for Diabetes Mellitus 2 POINTS for Prior Stroke or TIA1 or TE2

1 POINT for Vascular Disease3

1 POINT for Age 65-74 years1 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

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

1TIA = Transient ischemic attack; 2TE = Thromboembolism; 3Prior myocardial infarction, peripheral artery disease, aortic plaque

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

RISK FACTOR SCORE MAJOR BLEEDS (%/YR)

0 1.13

1 1.02

2 1.88

3 3.74

4 8.70

5 12.50

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

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

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

CHADS2 = 0 CHADS2 = 1 CHADS2 ≥ 2

No anti-thrombotic

No additional risk factors for

stroke

INCREASING STROKE RISK

ASA OAC* OAC* OAC

OAC = Oral anticoagulantASA = 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)

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 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 [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 110mg3.11%/yr for dabigatran 150mg 3.36%/yr for warfarin groupDabigatran 110mg vs warfarin: RR 0.80; 95%CI[0.69-0.93]; P=0.003Dabigatran 150mg vs warfarin: RR 0.93; 95%CI [0.81-1.07]; P=0.31Dabigatran 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 20mg14.5%/yr for warfarin groupHR 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 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.

Recent Oral Anticoagulation Trials:Stroke or Systemic Embolism

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

THE NEW ORAL ANTICOAGULANT AGENTS ARE CONSISTENTLY ASSOCIATED WITH A NUMERICALLY LOWER RISK FOR STROKE OR SYSTEMIC EMBOLISM COMPARED TO WARFARIN†

Data obtained from intention-to-treat analysis†Not intended as cross-trial comparison

Bid=twice daily; qd=daily

Dabigatran 110 mg bid

Dabigatran 150 mg bid

Rivaroxaban 20 mg qd

Apixaban 5 mg bid

P = 0.2943

P < 0.0001

P = 0.12

P = 0.01

P Value

New Agent Better Warfarin Better

0.50 0.75 1.00 1.501.25

Recent Oral Anticoagulation Trials:Hemorrhagic Stroke

THE NEW ORAL ANTICOAGULANTS ARE CONSISTENTLY ASSOCIATED WITHA NUMERICALLY LOWER RISK OF HEMORRHAGIC STROKE COMPARED WITH WARFARIN†

Data obtained from intention-to-treat analysis†Not intended as cross-trial comparison

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

Dabigatran 110 mg bid

Dabigatran 150 mg bid

Rivaroxaban 20 mg qd

Apixaban 5 mg bid

P < 0.001

P < 0.001

P = 0.24

P < 0.001

P Value

Bid=twice daily; qd=daily

New Agent Better Warfarin Better

0.00 0.25 0.50 1.000.75 1.25

HR (95% CI)

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;365:981-992. 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.

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

Early Risk of Stroke after Discharge fromthe Emergency Department among Patients with a First-ever TIA

CUMULATIVE % OF PATIENTS

READMITTED WITH STROKE

0

2

4

6

8

10

0 20 40 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 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

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, 2012Bytzer 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

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.

Apixaban Dabigatran RivaroxabanConcomitant 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 anticoagulantsClinically significant active bleedingRecent 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 ketoconazoleConcomitant use with any other anticoagulantsProsthetic valve anticoagulationHemorrhagic manifestationsLesions 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, breastfeedingConcomitant treatment with any other anticoagulantsRecent 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

Dabigatran Etexilate-specific Care

Weitz et al Circulation 2012.

Assess coagulation Do not use INR testing Use aPTT and/or diluted TT (HEMOCLOT®) every 3 hours Use test results to guide treatment decisions

aPTT = activated partial thromboplastin time; BID = twice daily; INR = international normalized ratio; TT = thrombin time; ULN = upper limit of normal

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

Management of Moderate-Severe Bleeding

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;126:2428-32.

Identify source of bleedingVerify time of the last dabigatran dose – if within 0-4 hours, consider oral activated charcoalMeasure anticoagulant activity (aPTT and/or Hemoclot, if available)Measure creatinine, calculate creatinine clearance and estimate dabigatran half-lifeLocal/surgical hemostasis as appropriateGeneral 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 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)

*If bleeding cannot be managed (hemodynamicallyunstable, renal impairment), consider hemodialysis

(toxin protocol, heparin free) for 6 to 8 hours or charcoal filtration

- Monitor aPTT and/or Hemoclot every 3 hours

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

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.

0 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

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 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