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MANAGEMENT OF ANTICOAGULATION FOR ATRIAL FIBRILLATION 2014 1.CONFIRM ATRIAL FIBRILLATION/FLUTTER 2.DETERMINE STROKE RISK 3.CHOOSE ANTICOAGULANT AGENT,

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Presentation on theme: "MANAGEMENT OF ANTICOAGULATION FOR ATRIAL FIBRILLATION 2014 1.CONFIRM ATRIAL FIBRILLATION/FLUTTER 2.DETERMINE STROKE RISK 3.CHOOSE ANTICOAGULANT AGENT,"— Presentation transcript:

1 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.

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

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6 Stroke risk was equivalent with intermittent and sustained NVAF in SPAF trials1

7 Points Annual Stroke Risk95% Confidence Interval 01.9%1.2-3.0 12.8%2.0-3.8 24.0%3.1-5.1 35.9%4.6-7.3 48.5%6.3-11.1 512.5%8.2-17.5 618.2%10.5-27.4 CHADS 2 Risk Score and Corresponding Risk for Stroke in AF Patients Not Treated With Anticoagulant Therapy

8 CHA 2 DS 2 -VASc Congestive heart failure1 Hypertension 1 Age > 752 Diabetes 1 Stroke/TIA/TE2 Vascular disease (MI, PAD, aortic plaque)1 Age 65-741 Female sex1

9 CHA 2 DS 2 -VAScStroke rate %/year 00% 11.3% 22.2% 33.2% 44.0% 56.7% 69.8% 79.6% 86.7% 915.2%

10 HAS-BLED Hypertension=1 Abnormal renal/liver function=1 Stroke=1 Bleeding history or disposition=1 Labile INR=1 Elderly=1 Drugs/Alcohol=1

11 Clinically Relevant Bleeding Major Bleeding 07%1% 18%1% 211%2% 316%3% 415%3% >5>538%8% HAS-BLED

12 Points Annual Stroke Risk 95% Confidence Interval 01.9%1.2-3.0 12.8%2.0-3.8 24.0%3.1-5.1 35.9%4.6-7.3 48.5%6.3-11.1 512.5%8.2-17.5 618.2%10.5-27.4 Clinically Relevant Bleeding Major Bleeding 07%1% 18%1% 211%2% 316%3% 415%3% >5>538%8% CHADS 2 HAS-BLED

13 ScoreRiskAnticoagulation Considerations 0LowAspirin (81-325 mg) daily or none 1ModerateAspirin 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 greaterModerate or HighWarfarin (INR 2.0-3.0) or dabigatran (Pradaxa) or rivaroxaban (Xarelto) or apixaban (Eliquis)

14 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 XIX IXa VIIIa Va II FibrinFibrinogen Adapted from Weitz et al, 2005; 2008 Dabigatran

15 PRADAXA 150 mg twice daily was significant in reducing the risk of stroke and systemic embolism an additional 35% vs warfarin PRADAXA= DABIGATRAN

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

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22 Managing anticoagulant effects of PRADAXA in cases of hemorrhagic complications

23 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 XIX IXa VIIIa Va II FibrinFibrinogen Adapted from Weitz et al, 2005; 2008

24 Primary Efficacy Outcome Stroke and non-CNS Embolism Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population No. at risk: Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634 Warfarin 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 Cumulative event rate (%) Rivaroxaban Warfarin Event Rate 1.712.16

25 Primary Safety Outcomes RivaroxabanWarfarin Event Rate HR (95% CI) P- value Major and non-major Clinically Relevant 14.9114.521.03 (0.96, 1.11)0.442 Major3.603.451.04 (0.90, 1.20)0.576 Non-major Clinically Relevant 11.8011.371.04 (0.96, 1.13)0.345 Event Rates are per 100 patient-years Based on Safety on Treatment Population

26 Bleeding Sites CrCl 30–49 ml/minCrCl ≥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) 2.881.770.021.791.120.0002 Intracranial0.710.880.540.440.710.02 Macroscopic haematuria 0.050.180.220.280.190.21 Bleeding associated with non-cardiac surgery 0.240.420.310.150.190.61 Intra-articular0.000.230.990.180.170.98 Epistaxis0.190.090.400.100.130.53 *Major bleeding per 100 pt-yrs of follow-up

27 RivaroxabanWarfarin Event Rate HR (95% CI)P-value Vascular Death, Stroke, Embolism 4.514.810.94 (0.84, 1.05)0.265 Stroke Type Hemorrhagic Ischemic Unknown Type 0.26 1.62 0.15 0.44 1.64 0.14 0.58 (0.38, 0.89) 0.99 (0.82, 1.20 1.05 (0.55, 2.01) 0.012 0.916 0.871 Non-CNS Embolism0.160.210.74 (0.42, 1.320.308 Myocardial Infarction1.021.110.91 (0.72, 1.16)0.464 All Cause Mortality Vascular Non-vascular Unknown Cause 4.52 2.91 1.15 0.46 4.91 3.11 1.22 0.57 0.92 (0.82, 1.03) 0.94 (0.81, 1.08) 0.94 (0.75, 1.18) 0.80 (0.57, 1.12) 0.152 0.350 0.611 0.195 Key Secondary Efficacy Outcomes Event Rates are per 100 patient-years Based on Intention-to-Treat Population

28 Please see the full Prescribing Information, including Boxed WARNINGS, available at this event. XARELTO ® (rivaroxaban) Is Administered With Once-daily Dosing CrCl (mL/min) Recommended Once-daily Dose of XARELTO ® >5020 mg 15 to 5015 mg* <15Avoid use 28 ♦ 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.

29 Please see the full Prescribing Information, including Boxed WARNINGS, available at this event. XARELTO  (rivaroxaban): Drug-Drug Interaction Profile 29 Drugs (examples) PK/PD EffectsRecommendation 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.

30 Please see the full Prescribing Information, including Boxed WARNINGS, available at this event. Interrupting rivaroxaban Prior 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

31 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.

32 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 1.5 Apixaban Xa IIa TF/VIIa XIX IXa VIIIa Va II FibrinFibrinogen

33 Kaplan–Meier Curves for the Primary Efficacy and Safety Outcomes. Granger CB et al. N Engl J Med 2011;365:981-992.

34 Bleeding Outcomes and Net Clinical Outcomes. Granger CB et al. N Engl J Med 2011;365:981-992.

35 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.

36 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.

37 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.

38 PradaxaXareltoEliquis 150mg bid Cr.Cl >30 75mg bid Cr.Cl 15-30 Avoid Cr.Cl <15 20mg Cr.Cl >50 15mg Cr.Cl 15-50 Avoid Cr.Cl <15 5mg bid 2.5mg bid if 2 or more: >80, creat 1.5 With or without foodLargest mealWith or without food Avoid with rifampin, quinidine If 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.

39 PRADAXAXARELTOELIQUIS Converting from warfarin: start when INR<2 Converting from warfarin: start when INR<3 Converting from warfarin: start when INR<2 Rapid onset No monitoring (PTT) Rapid onset No monitoring (INR, PTT, anti-factor Xa activity) Rapid onset No monitoring (INR, PTT, anti-factor Xa activity) 1-2 day hold if Cr.Cl >50 3-5 if Cr.Cl <50 At least 24 hoursAt least 24 hours low risk At least 48 hours high risk Baseline Cr.Cl, at least 6 monthly Extreme caution with epidural catheters Cannot crushCan crush (apple sauce)Cannot crush

40 PRADAXAXARELTOELIQUIS DVT, PE, extended Hip and knee prophylaxis


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