ThrombosisDr. Peter J. Lin

Director Primary Care Initiatives

Canadian Heart Research Centre

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Platelet

Fibrin

Red blood cell

Fast Flowing

Platelets Stick First

Slow Flow

Coagulation First

Stroke Burden Of Atrial Fibrillation

60%

20%

0%

20%

40%

60%

80%

100%

Disabling Fatal

QoL: quality of life.

1. Gladstone et al. Stroke. 2009;40:235; 2. Gage et al. Arch Intern Med. 1996;156:1829;

3. Solomon et al. Stroke. 1994;25:1721.

9

Impact of ischemic stroke in patients with AF (n=597)1

Many patients view QoL

following a severe stroke as

equal to or worse than

death2,3

Next

The Impact of Atrial Fibrillation (AF) in Canada

10

• Approximately 350,000 Canadians are living with AF1

‒ 25% of Canadians >40 years of age will develop AF2

• AF increases the risk of ischemic stroke by 3 to 5 times1,3

‒ AF-related strokes are associated with higher rates of morbidity and mortality

than non-AF-related strokes4,5

• With AF, annual stroke rate is 4.5%6

‒ About 16,000 AF-related strokes per year in Canada (about 20% of all strokes7)

1. Canadian Heart and Stroke Foundation. https://www.heartandstroke.ca/heart/conditions/atrial-fibrillation Accessed January 9, 2017. 2. Lloyd-Jones DM, et al. Circulation 2004;110:1042–6.

3. European Heart Rhythm Association, et al. Eur Heart J 2010;31:2369-429. 4. Dulli DA, et al. Neuroepidemiology 2003;22:118-23. 5. Marini C, et al. Stroke 2005;36:1115-9.

6. [No authors listed]. Arch Intern Med 1994;154:1449-57. 7. Wolf PA, et al. Stroke 1991;22:983-8.

Warfarin (Wisconsin Alumni Research Foundation)

• Warfarin is the most widely used coumarin derivative

• Originally found in sweet clover

Sweet clover

100% 50% 0% -50% -100%

AFASAK-1 (n=671)

SPAF (n=421)

BAATAF (n=420)

CAFA (n=378)

SPINAF (n=571)

EAFT (n=439)

All Trials (n=2900)

Warfarin Better Warfarin Worse

64%

Stroke Prevention in AF 6 Trials of Warfarin vs. Placebo

13Hart RG, et al. Ann Intern Med 2007;146:857-67.

AFASAK: Atrial Fibrillation, Aspirin, AntiKoagulation; SPAF: Stroke Prevention in Atrial Fibrillation;

BAATAF: Boston Area Anticoagulation Trial for Atrial Fibrillation; CAFA: Canadian Atrial Fibrillation Anticoagulation;

SPINAF: Stroke Prevention in Nonrheumatic Atrial Fibrillation; EAFT: European Atrial Fibrillation Trial

Warfarin Has Been Shown to Reduce Stroke Risk in AF

Hylek EM, et al. NEJM 1996;335:540-546.

INR below 2.0 results in a higher risk of

stroke

Lowest Effective Intensity for Warfarin Therapy for Stroke Prevention in Atrial Fibrillation

Hylek, et al, studied the risk of intracranial hemorrhage in outpatients treated with warfarin. They determined that an intensity of anticoagulation expressed as a prothrombin time ratio (PTR) above 2.0 (roughly corresponding to an INR of 3.7 to 4.3) resulted in an increase in the risk of bleeding.

Adapted from: Hylek EM, Singer DE, Ann Int Med

1994;120:897-902

Risk of Intracranial Hemorrhage in Outpatients

Copyright ©2006 American Heart Association

Fuster, V. et al. Circulation 2006;114:e257-e354

Adjusted odds ratios for ischemic stroke and intracranial bleeding in relation to intensity of anticoagulation

INR 2-3

Warfarin Reduce Stroke Risk in AF 64%

Warfarin – mechanism of action

Vitamin K

Synthesis of functional

coagulation factors

VII

IX

X

II

Warfarin – mechanism of action

Vitamin K

Synthesis of non-functional

coagulation factors

VII

IX

X

II

Warfarin

Warfarin – mechanism of action

Food interactions

Green leafy vegetables counteract effects of warfarin

• Foods with high amounts of vitamin K, e.g:

‒ Cauliflower

‒ Green cabbage

‒ Seaweed (1350)

‒ Broccoli (270)

‒ Green tea

‒ Turnip greens

‒ Soybean oil (often used to fry foods in restaurants)

‒ Raw spinach

Vitamin K

0

2

4

6

8

10

12

14

16

18

1 5 9 13 17 21 25 29 33 37 41 45 49 53 57 61

High Rates of Hemorrhage within 30 Days of Initiating Warfarin Therapy

22Gomes T, et al. CMAJ 2013;185:E121-7.

Incident rate of visits to hospital with hemorrhages in 30-day increments after the

start of warfarin therapy among older patients (≥ 66 yr) with AF

Rates are stratified by CHADS2 score at the start of treatment.

Inc

ide

nt

rate

of

he

mo

rrh

ag

e,

% p

er

pers

on

-year

Months

Overall Score 4-6Score 1

Clotting Cascade

II

VII

IX

X

protein C

protein S

• Vitamin K-dependent clotting factors have variable half-

lives

• Several days are required for maximal anticoagulant

effect of warfarin to be achieved

• Warfarin half-life is 2.5 days

Slow onset and offset of action

T½ 60 hours

4–6

24

48–72

8

30

Factors

Clotting Cascade

Direct Thrombin Inhibitor

(DTI)

Factor Xa inhibitor

26

Rate of Fatal Bleeding with NOACs

0.07

0.36 0.360.38

0.48

0.05

0.220.25

0.210.24

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

ARISTOTLE RE-LY

(D110 mg)

RE-LY

(D150 mg)

ENGAGE AF ROCKET-AF

Fa

tal B

lee

din

g E

ve

nts

(%

/ye

ar)

1. Apixaban (Eliquis) Product Monograph. Bristol-Myers Squibb Canada; 2. Dabigatran (Pradaxa) Product Monograph. Boehringer Ingelheim

Canada Ltd; 3. Giugliano et al. N Engl J Med. 2013;369:2093-104; 4. Rivaroxaban (Xarelto) Product Monograph.

Warfarin

Apixaban

Dabigatran 110 mg

Rivaroxaban

21 3

Fatal Bleeding is Reduced with NOACs vs. Warfarin with Rates <0.5%/year

Edoxaban

4

Dabigatran 150 mg

HR: 0.71

(0.25-1.95)

p=0.6183

HR: 0.61

(0.38-1.0)

p=0.0491

HR: 0.70

(0.44-1.12)

p=0.1338

HR: 0.55

(0.36-0.84)

p=0.006

HR: 0.50

(0.31-0.79)

p=0.003

2

*Not intended for cross study comparison

Other Bleeding Outcomes

27Giugliano RP, et al. N Engl J Med 2013;369:2093-104.

CRNM: clinically relevant nonmajor bleeding

Higher-dose edoxaban* vs. warfarin

0.55 (0.36-0.84)

p=0.006

0.47 (0.34-0.63)

p<0.001

1.23 (1.02-1.50)

p=0.03

0.51 (0.38-0.70)

p<0.001

0.86 (0.80-0.92)

p<0.001

Fatal

Intracranial

Gastrointestinal

Life-threatening

bleeding

Major or CRNM

*Dose reduced by 50% in selected pts

Warfarin betterEdoxaban better Hazard Ratio (95% CI)

1.0 2.00.10

Hazard ratio

Efficacy and Safety Benefits of NOACs vs. Warfarin from RCTs

Ruff CT, et al. Lancet 2014;383:955-62.

Ruff, Lancet, 2014, 383, 955

28

Stroke or systemic embolic events

Major bleeding

RR (95% CI) P

RE-LY (dabigatran 150 mg twice daily) 0.66 (0.53-0.82) 0.0001

ROCKET AF (rivaroxaban 20 mg once daily) 0.88 (0.75-1.03) 0.12

ARISTOTLE (apixaban 5 mg twice daily) 0.80 (0.67-0.95) 0.012

ENGAGE AF-TIMI 48 (edoxaban 60 mg once daily) 0.88 (0.75-1.02) 0.10

Combined (random) 0.81 (0.73-0.91) <0.0001

1.0 2.00.5Favours NOAC Favours Warfarin

Data are n/N, unless otherwise indicated. Heterogeneity: I2=47%; p=0.13. NOAC=non–vitamin K antagonist oral anticoagulants. RR=risk ratio.

RR (95% CI) P

RE-LY (dabigatran 150 mg twice daily) 0.94 (0.82-1.07) 0.34

ROCKET AF (rivaroxaban 20 mg once daily) 1.03 (0.90-1.18) 0.72

ARISTOTLE (apixaban 5 mg twice daily) 0.71 (0.61-0.81) <0.0001

ENGAGE AF-TIMI 48 (edoxaban 60 mg once daily) 0.80 (0.71-0.90) 0.0002

Combined (random) 0.86 (0.73-1.00) 0.06

Data are n/N, unless otherwise indicated. Heterogeneity: I2=83%; p=0.001. NOAC= non–vitamin K antagonist oral anticoagulants. RR=risk ratio.

1.02.00.5

Favours NOAC Favours Warfarin

Net Clinical Outcomes

29Giugliano RP, et al. N Engl J Med 2013;369:2093-104.

SEE: systemic embolic event

Higher-dose edoxaban* vs. warfarin

0.89 (0.83-0.96)

p=0.003

0.88 (0.81-0.97)

p=0.008

0.88 (0.81-0.96)

p=0.003

Stroke, SEE, death, major

bleeding

Disabling stroke, life-

threatening bleeding, death

Stroke, SEE, life-threatening

bleeding, death

Warfarin betterEdoxaban betterHazard ratio (95% CI)

1.00 1.500.50

Hazard ratio

0.75

*Dose reduced by 50% in selected pts

CHADS2 Score

1. JAMA. 2001;285(22):2864-2870. 2. Am J Med. 2010;123(6):484-488. 3. Can J Cardiol. 2012;28(2):125-136. 30

Quantifies stroke risk, aids in selection of antithrombotic therapy for risk

reduction

Letter Condition Points

C CHF 1

H Hypertension 1

A Age >75 years 1

D Diabetes 1

S2 Prior Stroke or TIA 2

CHADS2

score

Stroke rate per 100

patient-years

0 1.9

1 2.8

2 4.0

3 5.9

4 8.5

5 12.5

6 18.2

Can J Cardiol. 2016;32(10):1170-1185. 31

RECOMMENDATION:

We recommend that when

OAC therapy is indicated

for patients with non-

valvular AF, most patients

should receive dabigatran,

rivaroxaban, apixaban, or

edoxaban…in preference

to warfarin

(Strong Recommendation,

High-Quality Evidence).

Despite Increasing Use of NOACs in AF Globally, Many Patients Still Remain Untreated or Inappropriately Treated

32Camm AJ, et al. Heart 2017;103:307-14.

Evolution in Baseline Treatment for Patients Enrolled in Sequential Cohorts of GARFIELD-AF

Proportion of newly

diagnosed patients

with AF not prescribed

OAC

0

10

20

30

40

50

60

70

80

90

100

Cohort 1 Cohort 2 Cohort 3 Cohort 4

Pro

po

rtio

n o

f P

ati

en

ts o

n

Tre

atm

en

t, %

2010-2011

(n=5311)

2011-2013

(n=11,562)

2013-2014

(n=11,343)

2014-2015

(n=10,923)

12.4

30.2

4.2

53.2

11.5

26.1

13.8

48.5

12.9

20.1

26.3

40.8

12.4

16.6

37.0

34.0

VKA ± AP Fxa/DTI ± AP AP None

57.4%

29.0%

GARFIELD-AF: Global Anticoagulant Registry in the Field–Atrial Fibrillation; AP: antiplatelet; DTI: direct thrombin inhibitor; Fxa: factor Xa inhibitor; VKA: vitamin K antagonist

Proportion of newly

diagnosed patients

with AF prescribed

OAC

71.0%

42.6%

Total Drug Exposure (AUC) with Declining Renal

Function

≥80 50-79 30-49 <30

AU

C R

atio

vs.

No

rma

l R

en

al Fu

nc

tio

n

0

1

2

3

4

5

6

7

≥80 50-79 30-49 <30 ≥80 50-79 30-49 <30

Rivaroxaban4Apixaban1 Dabigatran2

Creatinine Clearance (mL/min)

Normal Renal Function: ≥80 mL/min; Mild Renal Impairment: 50-79 mL/min

Moderate Renal Impairment: 30-49 mL/min; Severe Renal Impairment: <30 mL/min

33

1. Apixaban (Eliquis) Product Monograph. Bristol-Meyers Squibb Canada; 2. Dabigatran (Pradaxa) Product Monograph.

Boehringer Ingelheim Canada Ltd.; 3. Edoxaban (Lixiana) Product Monograph. Progress Therapeutics; 4. Rivaroxaban (Xarelto)

Product Monograph. Bayer Inc.

≥80 50-79 30-49 <30

Edoxaban3

Common Methods for Assessing Renal

Function • Cockcroft-Gault

– Estimates CrCl based on age, weight, sex and creatinine

– Recommended equation for drug dose adjustments in

patients with renal impairment

• Modification of Diet in Renal Disease (MDRD)

– Estimates GFR based on age, race, sex and creatinine

– More accurately estimates renal function vs. Cockcroft-Gault

– Loses precision in patients with normal renal function and

might falsely suggest CKD

CKD: chronic kidney disease; CrCl: creatinine clearance; GFR: glomerular filtration rate.

1. Macle et al. Can J Cardiol. 2015;31:1207-18. 34

Kate’s eGFR according to MDRD:

52 mL/min/1.73 m2

Equations compared to Inulin

35Clin J Am Soc Nephrol 4: 899–906, 2009. doi: 10.2215/CJN.05371008

Cockcroft-Gault MDRD

GFR

REAL GFR

Calc GFR

Equations compared to Inulin

36Clin J Am Soc Nephrol 4: 899–906, 2009. doi: 10.2215/CJN.05371008

Cockcroft-Gault MDRD

Equations compared to Inulin

37Clin J Am Soc Nephrol 4: 899–906, 2009. doi: 10.2215/CJN.05371008

Cockcroft-Gault MDRD

Stroke Prevention in Patients with Renal

Impairment

How should we be treating patients with AF and renal impairment?

Therapeutic Choices for the Prevention of Stroke in Patients with CKD

*Consider Dabigatran 110 mg BID if age >80 or if the patient is at higher risk of bleeding, including elderly ≥75 years with ≥1 risk factor;

†Consider Apixaban 2.5 mg BID if 2 of 1) age ≥80 years, 2) body weight ≤60 kg, or 3) creatinine ≥133 μmol/L; ‡ARISTOTLE included a small

number of patients (1.5%) with a CrCl as low as 25 ml/min; ‖Dose adjusted warfarin has been used, but data regarding safety and

efficacy is conflicting; ¶No published studies; product monographs suggest the drug is contraindicated for this level of renal function.

1. Apixaban (Eliquis) Product Monograph. Bristol-Myers Squibb Canada; 2. Dabigatran (Pradaxa) Product Monograph. Boehringer

Ingelheim Canada Ltd.; 3. Edoxaban (Lixiana) Product Monograph. Progress Therapeutics; 4. Rivaroxaban (Xarelto) Product Monograph.

Bayer Inc; 5. Warfarin (Coumadin) Product Monograph. Bristol-Myers Squibb Canada.39

CrCl

(mL/min)

Apixaba

n1Dabigatran2 Edoxaban3 Rivaroxaban4 Warfarin5

>50 5 mg BID 150 mg BID* 60 mg daily 20 mg daily Dose

adjusted

for

INR 2.0-3.030-49

5 mg BID

(consider

2.5 BID)†

150 mg BID* 30 mg daily 15 mg daily

15-29 Limited

data‡

No RCT

data

Limited

data

No RCT

data

No RCT

data‖

<15

or dialysis

No RCT

data¶

No RCT

data¶

No RCT

data¶

No RCT

data¶

No RCT

data‖

Patients with AF and eGFR

≤30 mL/min

Patients with AF and eGFR

>30mL/minWarfarin

Apixaban

Dabigatran

Rivaroxaban

Edoxaban

CCS Guidelines Recommend NOACs for Eligible AF Patients

with eGFR ≥30 mL/min

40CCS: Canadian Cardiovascular Society; eGFR: estimated glomerular filtration rate.

1. Verma et al. Can J Cardiol. 2014:30;1114-30.

Dabigatran2

Dosing Algorithms in AFApixaban1

41

1. Apixaban (Eliquis) Product Monograph. Bristol-Meyers Squibb Canada; 2. Dabigatran (Pradaxa) Product Monograph.

Boehringer Ingelheim Canada Ltd.; 3. Edoxaban (Lixiana) Product Monograph. Progress Therapeutics; 4. Rivaroxaban

(Xarelto) Product Monograph. Bayer Inc.

Edoxaban3 Rivaroxaban4

Apixaban Dosing Algorithm

eCrCl: estimated creatinine clearance.

1. Apixaban (Eliquis) Product Monograph. Bristol-Meyers Squibb Canada. 42

Return to slide

Patient has risk factor for stroke

Estimate CrCl

≥25

mL/min

5 mg

BID

2.5 mg

BID

<15 mL/min

Not

recommendedCheck Age

Check

Weight

Check

Serum

Creatinine

≥80 years ≤60 kg≥133

micromol/L

If ≥2

features

If ≤1

features

≥15-24

mL/min

No dosing

recommendation

can be made*

*In patients with eCrCl

15-24 mL/min, no dosing

recommendation can

be made as clinical

data are very limited

Use 2.5mg bid(2 or more)

Age 80Weight 60kgCreatinine 133

Dabigatran Dosing Algorithm

Return to slide 431. Dabigatran (Pradaxa) Product Monograph. Boehringer Ingelheim Canada Ltd.

Patient has risk factor for

stroke

Estimate CrCl

<30 mL/min 30-50 mL/min>50

mL/min

Age

<75 years

Age

75-79

years

Age

≥80 years

150

mg

BID

110

mg

BID

150mg BID

Contra-indicated

150 mg BID

[Patients

with ≥1 risk

factor for

bleeding –

110 mg BID]

150

mg

BID

Is the patient at higher risk

of bleeding?

NoYes

110

mg

BID

Use 110mgBleeding risk Age > 80

Edoxaban Dosing Algorithm

*except amiodarone and verapamil.

1. Edoxaban (Lixiana) Product Monograph. Progress Therapeutics44Return to Slide

Patient has risk factor for stroke

Estimate CrCl

>50 mL/min

60 mg

OD

30-50 mL/min

30 mg OD

<30 mL/min

Not

recommended

Check

Weight

≤60 kg

Check

Medications

Concomitant

P-gp inhibitor?*

30 mg OD

30 mg OD

Use 30mg eGFR 30-50Weight 60Drug Pglycoprotein blockers

Cyclosporine, Dronedarone, Ketoconazole, Quinidine, Erythromycin

Rivaroxaban Dosing Algorithm

1. Rivaroxaban (Xarelto) Product Monograph. Bayer Inc. 45Return to Slide

Patient has risk factor for stroke

Estimate CrCl

30-49 mL/min >50 mL/min

20 mg

OD15 mg

OD

<30 mL/min

Not

recommended

Rivaroxaban is the only NOAC that prospectively studied a reduced dose based solely on renal function7

Use 15mg eGFR 30-50

Dose Considerations for the NOACs

NOAC Usual Starting Dose Dose Adjustment Criteria

Apixaban1 5 mg BID

2.5 mg BID if any 2 of the following criteria:

- Age ≥80 years

- Body weight ≤60 kg

- Creatinine ≥133 μmol/L

Dabigatran2 150 mg BID

110 mg BID if:

- Age ≥80 years

- At higher risk of bleeding, including elderly

≥75 years with ≥1 risk factor

Edoxaban3 60 mg QD

30 mg QD if:

- CrCl 30 to 50 mL/min

- Body weight ≤60 kg

- Concomitant use of P-gp Inhibitors except

amiodarone and verapamil

Rivaroxaban4 20 mg QD 15 mg QD if CrCl 30 to 49 mL/min

1. Apixaban (Eliquis) Product Monograph. Bristol-Myers Squibb Canada; 2. Dabigatran (Pradaxa) Product Monograph. Boehringer

Ingelheim Canada Ltd; 3. Edoxaban (Lixiana) Product Monograph. Progress Therapeutics; 4. Rivaroxaban (Xarelto) Product

Monograph. Bayer Inc. 46

Bleeding Risks for Invasive/Surgical Procedures

1. Macle et al. CJC. 2016;32:1170-85;

2. 2016 CCS AF Guidelines Corrigendum (Nov 29, 2016). 47

REQUIRES Anticoagulation Interruption1,2

High risk

• Any surgery or procedure with neuraxial (spinal or

epidural) anesthesia

• Neurosurgery (intracranial or spinal)

• Cardiac surgery (e.g. CABG, heart valve

replacement)

• Major intra-abdominal surgery

• Major vascular surgery (e.g. aortic aneurysm repair,

aortofemoral bypass)

• Major orthopedic surgery (e.g. hip or knee

replacement)

• Lung resection surgery

• Urological surgery (e.g. prostatectomy, bladder

tumour resection)

• Extensive cancer surgery (e.g. pancreas, liver)

• Intestinal anastomosis surgery

• Reconstructive plastic surgery

• Selected procedures (e.g. kidney biopsy, prostate

biopsy, cervical cone biopsy, pericardiocentesis,

colonic polypectomy)

DOES NOT REQUIRE Anticoagulation Interruption1,2

Low risk

• Dental extractions (1 or 2 teeth), endodontic (root

canal) procedure,

• subgingival scaling or other cleaning

• Cataract surgery

• Dermatologic procedures (e.g. biopsy)

• Gastroscopy or colonoscopy without biopsies

• Coronary angiography

• Permanent pacemaker insertion or internal

defibrillator placement (if bridging anticoagulation is

not used)

• Selected procedures (e.g. thoracentesis,

paracentesis, arthrocentesis)

REQUIRES Anticoagulation Interruption1,2

Intermediate risk

• Other intra-abdominal surgery (e.g. laparoscopic

cholecystectomy, hernia repair)

• Other general surgery (e.g. breast)

• Other intrathoracic surgery

• Other orthopedic surgery

• Other vascular surgery

• Non-cataract ophthalmologic surgery

• Gastroscopy or colonoscopy with biopsies

• Selected procedures (e.g. bone marrow biopsy,

lymph node biopsy)

• Complex dental procedure (e.g. multiple tooth

extractions)

Pre-operative Management of Patients

Receiving a NOAC

48

Low Risk of BleedingIntermediate or

High Risk of Bleeding

1 Day Before 3 Days Before

Dabigatran1

30 to ≤50 mL/min

SKIP 6 DOSES

Apixaban1

≥30 mL/min

SKIP 2 DOSES

Dabigatran1

≥50 mL/min

SKIP 2 DOSES

Rivaroxaban1

≥30 mL/min

SKIP 1 DOSE

Edoxaban2,3

≥30 mL/min

SKIP 1 DOSE

2 Days Before

Apixaban1

≥30 mL/min

SKIP 4 DOSES

Dabigatran1

≥50 mL/min

SKIP 4 DOSES

Rivaroxaban1

≥30 mL/min

SKIP 2 DOSES

Edoxaban2,3

≥30 mL/min

SKIP 2 DOSES

5 Days Before

Dabigatran1

30 to ≤50 mL/min

SKIP 10 DOSES

Timing of LAST Dose Before Procedure

1. Thrombosis Canada. New/Novel Oral Anticoagulants (NOACs): Peri‐operative Management. Available from:

http://thrombosiscanada.ca/wp-content/uploads/2016/07/21_NOACs-Peri-Operative-Management_2016July13-FINAL.pdf ; 2. Edoxaban

(Lixiana) Product Monograph. Progress Therapeutics; 3. Consensus recommendations of the Planning Committee.

Post-operative Management of Patients

Receiving a NOAC

1. Thrombosis Canada. New/Novel Oral Anticoagulants (NOACs): Peri‐operative Management. Available from:

http://thrombosiscanada.ca/wp-content/uploads/2016/07/21_NOACs-Peri-Operative-Management_2016July13-FINAL.pdf; 2. Edoxaban

(Lixiana) Product Monograph. Progress Therapeutics49

Drug Renal Function

Suggested Timing for Resuming NOAC

Low Risk

of Bleeding

Intermediate or High

Risk of Bleeding

Apixaban1 24 hours after surgery 48 hours after surgery

Dabigatran1 24 hours after surgery 48 hours after surgery

Edoxaban2 Once adequate hemostasis has been established

Rivaroxaban1 24 hours after surgery 48 hours after surgery

Bridging Not Required for NOACs

“Bridging (LMWH or UFH) is not required for NVAF patients on

NOAC undergoing elective surgery or invasive procedures

requiring interruption of anticoagulation”

Consider bridging therapy in ANY post-operative patient whose

OAC therapy cannot be restarted within 72 hours2

50LMWH: low molecular weight heparin; NVAF: non-valvular atrial fibrillation; UFH: unfractionated heparin.

1. Macle et al. CJC. 2016;32:1170-85; 2. Douketis et coll. NEJM. 2015;373:823-33.

2016 CCS Guidelines for the Management of AF1

Thrombosis Canada

Xa inhibitors vs. Warfarin for ischemic stroke, intracranial hemorrhage or the combination of both

Apixaban Warfarin HR (95% CI)

apixaban vs. warfarin

HR (95% CI)

apixaban vs. warfarinRate (%/year) Rate (%/year)

ICH 0.38 0.97 0.38 (0.17–0.88)*

Ischemic

stroke0.56 0.51 1.13 (0.49–2.63)

Combined 0.89 1.44 0.63 (0.35–1.12)

0.125 0.25 0.5 1 2 4

Favorsapixaban

Favors warfarin

*p<0.05

Rivaroxaban Warfarin HR (95% CI)

rivaroxaban vs.

warfarin

HR (95% CI)

rivaroxaban vs. warfarinRate (%/year) Rate (%/year)

ICH 0.49 0.96 0.53 (0.35–0.79)*

Ischemic

stroke0.54 0.83 0.71 (0.47–1.07)

Combined 0.95 1.6 0.61 (0.45–0.82)*

0.125 0.25 0.5 1 2 4Favors

rivaroxabanFavors

warfarin

Coleman CI, Antz M, Simard E, et al. Real-world evidence on stroke prevention in patients with atrial fibrillation in the United States.

Presented at: European Cardiac Arrhythmia Society Congress. April 17, 2016. Paris, France.

NOAC adherence clinically-relevant?Dabigatran

0.95

1.00

1.05

1.10

1.15

Mortality/stroke Stroke Non-fatal bleeding event

Ha

zard

ra

tio

/10

% d

ecr

ea

se in

PD

C

1.13

95%CI, 1.08–1.191.13

95%CI, 0.97–1.33

1.04

95%CI, 0.94–1.14

5376 US veterans with NVAF (71.3±9.7 years; 98.3% were men and mean CHADS2 score was 2.4±1.2; mean PDC 84%±22%; 27.8% with a PDC <80%; median follow-up of 244 days) initiated on dabigatran from October 2010 to September 2012

Non-adherence is

associated with worse

outcomes during NVAF

NOAC treatment

Am Heart J. 2014;167:810-7.

XARELTO Product Monograph

XARELTO 10 mg – 100% with or without food

XARELTO 20mg – 66% without food,

39% increase with food

XARELTO 15 mg and 20 mg tablets should be

taken with food

Objectives

54

To determine in stable CV disease, whether:

•Aspirin 100 mg od

•Rivaroxaban 5 mg bid

•Rivaroxaban 2.5 mg bid + aspirin 100 mg od

Outcome: CV death, stroke or myocardial infarction

And whether: Pantoprazole compared with placebo reduces upper GI events (ongoing)

COMPASS design

Aspirin 100 mg od

Rivaroxaban 5 mg bid

RRun-in

(aspirin)

55

Rivaroxaban 2.5 mg bid

+ aspirin 100 mg od

Stable CAD or PAD2200 Events3-4 years

Baseline characteristics

56

CharacteristicRivaroxaban + aspirin Rivaroxaban Aspirin

N=9,152 N=9,117 N=9,126

Age, yr 68 68 68

Blood pressure, mmHg 136/77 136/78 136/78

Total cholesterol, mmol/L 4.2 4.2 4.2

CAD 91% 90% 90%

PAD 27% 27% 27%

Diabetes 38% 38% 38%

Lipid-lowering 90% 90% 89%

ACE-I or ARB 71% 72% 71%

Follow up, adherence

57

• On February 6, 2017 the Data and Safety Monitoring Board recommended discontinuation of rivaroxaban/aspirin arms for clear evidence of efficacy (combination: Z= -4.59, P<0.00001; rivaroxaban: Z= -2.44, P=0.01)

• Close-out between March and June 2017

• Mean follow up 23 months

• Follow up 99.8% complete

Primary: CV death, stroke, MI

58

Primary components

59

Outcome

R + AN=9,152

AN=9,126

Rivaroxaban + Aspirin vs. Aspirin

N(%)

N(%)

HR(95% CI) p

CV death160

(1.7%)203

(2.2%)0.78

(0.64-0.96) 0.02

Stroke83

(0.9%)142

(1.6%)0.58

(0.44-0.76)<0.0001

MI178

(1.9%)205

(2.2%)0.86

(0.70-1.05)0.14

Secondary outcomes

13

Outcome

R + AN=9,152

AN=9,126

Rivaroxaban + Aspirin vs. Aspirin

N(%)

N(%)

HR(95% CI) P*

CHD death, IS, MI, ALI

329(3.6%)

450(4.9%)

0.72(0.63-0.83)

<0.0001

CV death, IS, MI, ALI

389(4.3%)

516(5.7%)

0.74(0.65-0.85)

<0.0001

Mortality313

(3.4%)378

(4.1%)0.82

(0.71-0.96)0.01

* pre-specified threshold P=0.0025

CAD and PAD Subgroups for primary outcome

Outcome

R + AN=9,152

AN=9,126

Rivaroxaban + Aspirin

vs. Aspirin

N (%) N (%) HR (95% CI)

CAD347

(4.2%)

460

(5.6%)

0.74

(0.65-0.86)

PAD126

(5.1%)174

(6.9%)0.72

(0.57-0.90)

14

Major bleeding

62

Outcome

R + AN=9,152

RN=9,117

AN=9,126

Rivaroxaban + Aspirin vs. Aspirin

Rivaroxaban vs. Aspirin

N (%) N (%) N (%) HR (95% CI)P

HR (95% CI)P

Major bleeding288

(3.1%)255

(2.8%)170

(1.9%)1.70

(1.40-2.05) <0.00011.51

(1.25-1.84) <0.0001

Fatal15

(0.2%)14

(0.2%)10

(0.1%)1.49

(0.67-3.33) 0.321.40

(0.62-3.15) 0.41

Non fatal ICH*21

(0.2%)32

(0.4%)19

(0.2%)1.10

(0.59-2.04) 0.771.69

(0.96-2.98) 0.07

Non-fatal othercritical organ*

42(0.5%)

45(0.5%)

29(0.3%)

1.43(0.89-2.29) 0.14

1.57(0.98-2.50) 0.06

* symptomatic

Net clinical benefit

63

Outcome

R + AN=9,152

AN=9,126

Rivaroxaban + Aspirin vs. Aspirin

N (%) N (%) HR (95% CI)P

Net clinical benefit(Primary + Severe bleeding

events)431

(4.7%)534

(5.9%)0.80

(0.70-0.91)0.0005