MANAGEMENT OF ANTICOAGULATION FOR ATRIAL FIBRILLATION 2014

1. CONFIRM ATRIAL FIBRILLATION/FLUTTER

2. DETERMINE STROKE RISK

3. CHOOSE ANTICOAGULANT AGENT, WITH ASSESSMENT OF BLEEDING RISK

4. DRUG INTERACTIONS, ANTIPLATELET AGENTS.

DOCTOR JOFFE IS ON THE SPEAKER’S BUREAU FOR BOEHRINGER-ENGELHEIM (PRADAXA)

Stroke risk was equivalent with intermittent andsustained NVAF in SPAF trials1

PointsAnnual Stroke Risk 95% Confidence Interval

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

CHADS2 Risk Score and Corresponding Risk for Stroke in AF Patients Not Treated With Anticoagulant Therapy

CHA2DS2-VASc

Congestive heart failure 1Hypertension 1Age > 75 2Diabetes 1Stroke/TIA/TE 2Vascular disease (MI, PAD, aortic plaque) 1Age 65-74 1Female sex 1

CHA2DS2-VASc Stroke rate %/year

0 0%

1 1.3%

2 2.2%

3 3.2%

4 4.0%

5 6.7%

6 9.8%

7 9.6%

8 6.7%

9 15.2%

HAS-BLED

• Hypertension=1• Abnormal renal/liver function=1• Stroke=1• Bleeding history or disposition=1• Labile INR=1• Elderly=1• Drugs/Alcohol=1

ClinicallyRelevant Bleeding

Major Bleeding

0 7% 1%

1 8% 1%

2 11% 2%

3 16% 3%

4 15% 3%

>5 38% 8%

HAS-BLED

Points

Annual Stroke Risk

95% Confidence Interval

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

ClinicallyRelevant Bleeding

Major Bleeding

0 7% 1%

1 8% 1%

2 11% 2%

3 16% 3%

4 15% 3%

>5 38% 8%

CHADS2 HAS-BLED

Score Risk Anticoagulation Considerations0 Low Aspirin (81-325 mg) daily or none

1 Moderate Aspirin daily or warfarin (INR to 2.0-3.0) or dabigatran (Pradaxa) or rivaroxaban (Xarelto) or apixaban (Eliquis), depending on factors such as patient preference

2 or greater Moderate or High Warfarin (INR 2.0-3.0) ordabigatran (Pradaxa) orrivaroxaban (Xarelto) or apixaban (Eliquis)

Pradaxa (dabigatran)

Direct, specific, competitive thrombin inhibitor

Half-life 12-17 hours

Uses P-gp transporter with bowel absorption

Clearance : 80% renal excretion Not a substrate of CYP 450

enzymes

Oral, twice daily dosing without need for coagulation monitoring

Xa

IIa

TF/VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

Adapted from Weitz et al, 2005; 2008

Dabigatran

PRADAXA 150 mg twice daily was significant in reducingthe risk of stroke and systemic embolism an additional 35% vs warfarinPRADAXA= DABIGATRAN

Significant risk reduction of both ischemic stroke and hemorrhagic stroke vs warfarin

Managing anticoagulant effects of PRADAXA in cases of hemorrhagic complications

Rivaroxaban (Xarelto)

Direct, specific, competitive factor Xa inhibitor

Half-life 5-13 hours

Clearance : 1/3 direct renal excretion 2/3 metabolism via CYP 450

enzymes

Oral, once daily dosing with largest meal without need for coagulation monitoring

Rivaroxaban

Xa

IIa

TF/VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

Adapted from Weitz et al, 2005; 2008

Primary Efficacy OutcomeStroke and non-CNS Embolism

Event Rates are per 100 patient-yearsBased on Protocol Compliant on Treatment Population

No. at risk:Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655

Warfarin

HR (95% CI): 0.79 (0.66, 0.96)

P-value Non-Inferiority: <0.001

Days from Randomization

Cu

mu

lati

ve e

ven

t ra

te (

%)

Rivaroxaban

Rivaroxaban Warfarin

Event Rate 1.71 2.16

Primary Safety Outcomes

Rivaroxaban Warfarin

Event Rate Event Rate HR

(95% CI)P-

value

Major and non-major Clinically Relevant

14.91 14.52 1.03 (0.96, 1.11) 0.442

Major 3.60 3.45 1.04 (0.90, 1.20) 0.576

Non-major Clinically Relevant

11.80 11.37 1.04 (0.96, 1.13) 0.345

Event Rates are per 100 patient-yearsBased on Safety on Treatment Population

Bleeding Sites

CrCl 30–49 ml/min CrCl ≥50 ml/min

Riva 15 mg

(N = 1474)

Warfarin

(N=1476)

P-

value

Riva 20 mg

(N=5637)

Warfarin

(N=5640)

P-

value

GI (upper, lower, and rectal)

2.88 1.77 0.02 1.79 1.12 0.0002

Intracranial 0.71 0.88 0.54 0.44 0.71 0.02

Macroscopic haematuria

0.05 0.18 0.22 0.28 0.19 0.21

Bleeding associated with non-cardiac surgery

0.24 0.42 0.31 0.15 0.19 0.61

Intra-articular 0.00 0.23 0.99 0.18 0.17 0.98

Epistaxis 0.19 0.09 0.40 0.10 0.13 0.53

*Major bleeding per 100 pt-yrs of follow-up

Rivaroxaban Warfarin

Event Rate Event Rate HR (95% CI) P-value

Vascular Death, Stroke, Embolism

4.51 4.81 0.94 (0.84, 1.05) 0.265

Stroke Type Hemorrhagic Ischemic Unknown Type

0.261.620.15

0.441.640.14

0.58 (0.38, 0.89)0.99 (0.82, 1.201.05 (0.55, 2.01)

0.0120.9160.871

Non-CNS Embolism 0.16 0.21 0.74 (0.42, 1.32 0.308

Myocardial Infarction 1.02 1.11 0.91 (0.72, 1.16) 0.464

All Cause Mortality Vascular Non-vascular Unknown Cause

4.522.911.150.46

4.913.111.220.57

0.92 (0.82, 1.03)0.94 (0.81, 1.08)0.94 (0.75, 1.18)0.80 (0.57, 1.12)

0.1520.3500.6110.195

Key Secondary Efficacy Outcomes

Event Rates are per 100 patient-yearsBased on Intention-to-Treat Population

Please see the full Prescribing Information, including Boxed WARNINGS, available at this event.

XARELTO® (rivaroxaban) Is AdministeredWith Once-daily Dosing

CrCl (mL/min)Recommended

Once-daily Dose of XARELTO®

>50 20 mg

15 to 50 15 mg*

<15 Avoid use

2828

♦ XARELTO® should be taken once daily with the evening meal– Coadministration of XARELTO® 15 mg and 20 mg with food

increases its bioavailability to approximately 100%

♦ If a dose of XARELTO® is not taken at the scheduled time, administer the dose as soon as possible on the same day

*Patients with CrCl 15 to 30 mL/min were not studied, but administration of XARELTO® 15 mg once daily is also expected to result in serum concentrations of XARELTO® similar to those in patients with normal renal function.

Please see the full Prescribing Information, including Boxed WARNINGS, available at this event. 29

XARELTO (rivaroxaban):Drug-Drug Interaction Profile

Drugs (examples) PK/PD Effects Recommendation

Combined P-gp and strong CYP3A4 inhibitors

Ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, conivaptan

Concomitant use increases XARELTO exposure and PD effects; significant increases in rivaroxaban exposure may increase bleeding risk

Avoid concomitant use

Combined P-gp and strong CYP3A4 inducers

Carbamazepine, phenytoin, rifampin, St. John’s wort

Concomitant use decreases XARELTO exposure and PD effects, which may decrease efficacy of XARELTO

Avoid concomitant use if these drugs must be coadministered

Combined P-gp and weak or moderate CYP3A4 inhibitors in the presence of renal impairment (CrCl 15 to 50 mL/min)

Amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, azithromycin, cimetidine, chloramphenicol

Based on simulated PK data, patients with renal impairment receiving XARELTO concomitantly with combined P-gp and weak or moderate CYP3A4 inhibitors may have significant increases in exposure compared with patients with normal renal function. Although increases in exposure can be expected, results from ROCKET AF, which allowed concomitant use of combined P-gp and weak or moderate CYP3A4 inhibitors, did not show an increase in bleeding in patients with CrCl 30 to <50 mL/min

Use only if potential benefit justifies risk

Abbreviations: CYP = cytochrome P450; PK/PD = pharmacokinetic/pharmacodynamic.

Please see the full Prescribing Information, including Boxed WARNINGS, available at this event.

Interrupting rivaroxabanPrior to Surgery or Intervention

♦ If anticoagulation must be discontinued to reduce the risk of bleeding with surgery, then XARELTO® should be stopped at least 24 hours before the procedure

♦ In deciding whether a procedure should be delayed until 24 hours after the last dose of XARELTO®, the increased risk of bleeding should be weighed against the urgency of intervention

♦ XARELTO® should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established– If oral medication cannot be taken after surgical intervention,

consider a parenteral anticoagulant– Wait at least 18 hours after last dose before removal of

epidural catheter, and do not restart until at least 6 hours after removal.

30

Please see the full Prescribing Information, including Boxed WARNINGS, available at this event.

Considerations for Managing Bleeding in Patients Receiving XARELTO® (rivaroxaban)

♦ A specific antidote for XARELTO® is not available– XARELTO® is not expected to be dialyzable due to high

plasma-protein binding– Protamine sulfate and vitamin K are not expected to affect the

anticoagulant activity of XARELTO®

– Use of procoagulant reversal agents, eg, PCC, APCC, or rFVIIa may be considered, but has not been evaluated in clinical trials

♦ There is no experience with antifibrinolytic agents in individuals receiving XARELTO®

♦ There is neither scientific rationale for benefit nor experience with systemic hemostatics in individuals receiving XARELTO®

31

Abbreviations: APCC = activated prothrombin complex concentrate; PCC = prothrombin complex concentrate; rFVIIa = recombinant factor VIIa.

Apixaban (ELIQUIS)

Direct, specific, competitive factor Xa inhibitor

Half-life 12 hours

Clearance : 27% direct renal excretion Biliary and direct intestinal

excretion P-gp transport

Oral, twice daily dosing without need for coagulation monitoring: 5mg bid. 2.5mg bid with at least 2 of: 80 or older, weight <60kg, creatinine >1.5

Apixaban

Xa

IIa

TF/VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

Kaplan–Meier Curves for the Primary Efficacy and Safety Outcomes.

Granger CB et al. N Engl J Med 2011;365:981-992.

Bleeding Outcomes and Net Clinical Outcomes.

Granger CB et al. N Engl J Med 2011;365:981-992.

APIXABAN DRUG INTERACTIONS

• Strong Dual Inhibitors of CYP3A4 and P-gp: Increase exposure to apixaban and increase the risk of bleeding.

Decrease the dose of ELIQUIS to 2.5 mg twice daily (e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin).

In patients already taking ELIQUIS at a dose of 2.5 mg twice daily, avoid coadministration with strong dual inhibitors of CYP3A4 and P- gp.

• Strong Dual Inducers of CYP3A4 and P-gp:

Decrease exposure to apixaban and increase the risk of stroke. Avoid concomitant use of ELIQUIS e.g., rifampin, carbamazepine,

phenytoin, St. John's wort.

APIXABAN

ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding.

ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be noncritical in location and easily controlled.

FDA POSITION FROM TRIALS

• Dabigatran significantly reduced stroke or systemic embolism, and ischemic stroke alone, with similar major bleeding versus warfarin.

• Rivaroxaban similar rates of stroke or embolism and major bleeding versus warfarin.

• Apixaban: significant reductions in stroke or systemic embolism, major bleeding and mortality compared to warfarin.

Pradaxa Xarelto Eliquis

150mg bid Cr.Cl >3075mg bid Cr.Cl 15-30Avoid Cr.Cl <15

20mg Cr.Cl >5015mg Cr.Cl 15-50Avoid Cr.Cl <15

5mg bid2.5mg bid if 2 or more:>80, <60kg, >creat 1.5

With or without food Largest meal With or without food

Avoid with rifampin, quinidineIf Cr.Cl 30-50, reduce dose to 75mg bid with Multaq and ketoconazole. If Cr.Cl <30, avoid Multaq and ketoconazole.Verapamil may increase levels

Avoid rifampin, carbamazepine, phenytoin, St. John’s wart. Avoid ketoconazole, traconazole, lopinavir/ritonavir, itonavir, indinavir/ritonavir, conivaptan. Avoid amiodarone,diltiazem, verapamil, Multaq, erythromycin, Ranexa, azithromycin, cimetidine if Cr.Cl 15-50

Avoid rifampin, carbamazepine, phenytoin, St. John’s wart. Reduce to 2.5mg bid with ketoconazole, itraconazole, Biaxan. If on 2.5mg bid, stop Eliquis.

PRADAXA XARELTO ELIQUIS

Converting from warfarin: start when INR<2

Converting from warfarin: start when INR<3

Converting from warfarin: start when INR<2

Rapid onsetNo monitoring(PTT)

Rapid onsetNo monitoring(INR, PTT, anti-factor Xa activity)

Rapid onsetNo monitoring(INR, PTT, anti-factor Xa activity)

1-2 day hold if Cr.Cl >503-5 if Cr.Cl <50

At least 24 hours At least 24 hours low riskAt least 48 hours high risk

Baseline Cr.Cl , at least 6 monthly

Baseline Cr.Cl, at least 6 monthly

Baseline Cr.Cl, at least 6 monthly

Extreme caution with epidural catheters

Extreme caution with epidural catheters

Extreme caution with epidural catheters

Cannot crush Can crush (apple sauce) Cannot crush

PRADAXA XARELTO ELIQUIS

DVT, PE, extended DVT, PE, extended DVT, PE, extended

Hip and knee prophylaxis

Hip and knee prophylaxis