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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
Recommended