6Stroke risk was equivalent with intermittent and sustained NVAF in SPAF trials1 Slide ID: 27040Stroke risk is equivalent with intermittent and sustained NVAFIn a longitudinal cohort study, Hart and colleagues analyzed stroke rates and predictors of stroke among 460 patients with intermittent AFib given aspirin in the Stroke Prevention in Atrial Fibrillation (SPAF) I-III studies, comparing them to participants with sustained Afib (n=1552)Study participants had documented sustained or recurrent AFib without mitral stenosis or prosthetic cardiac valves. Atrial fibrillation was categorized as intermittent if sinus rhythm was documented within 12 months prior to study entry for SPAF I and II participants and within three months for SPAF III participantsThis study demonstrated that intermittent AFib was associated with stroke rates comparable to that of sustained AFib. In addition, patients with intermittent AFib and sustained AFib had similar risk factors for strokeReference:Hart RG, Pearce LA, ,Rothbart RM, McAnulty JH, Asinger RW, Halperin JL. Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy. J Am Coll Cardiol. 2000;35:
7CHADS2 Risk Score and Corresponding Risk for Stroke in AF Patients Not Treated With Anticoagulant TherapyPointsAnnual Stroke Risk95% Confidence Interval1.9%12.8%24.0%35.9%48.5%512.5%618.2%
13ScoreRiskAnticoagulation ConsiderationsLowAspirin ( mg) daily or none1ModerateAspirin daily or warfarin (INR to ) or dabigatran (Pradaxa) or rivaroxaban (Xarelto) or apixaban (Eliquis), depending on factors such as patient preference2 or greaterModerate or HighWarfarin (INR ) ordabigatran (Pradaxa) orrivaroxaban (Xarelto) or apixaban (Eliquis)
14Pradaxa (dabigatran) TF/VIIa Xa IIa G w_script.ppt4/13/2017 6:30:35 PMPradaxa (dabigatran)TF/VIIaDirect, specific, competitive thrombin inhibitorHalf-life hoursUses P-gp transporter with bowel absorptionClearance :80% renal excretionNot a substrate of CYP 450 enzymesOral, twice daily dosing without need for coagulation monitoringXIXIXaVIIIaVaXaIIDabigatranIIaFibrinogenFibrinAdapted from Weitz et al, 2005; 2008
15PRADAXA 150 mg twice daily was significant in reducing the risk of stroke and systemic embolism an additional 35% vs warfarinPRADAXA= DABIGATRANSlide ID: 27051PRADAXA 150 mg twice daily was significant in reducing the risk of stroke and systemic embolism vs warfarinEffects of PRADAXA compared to warfarin were more apparent in patients with lower levels of INR controlThe graphic shown is a Kaplan-Meier curve estimate of time to the primary endpoint of first stroke or systemic embolism. As time progressed, cumulative risk in subjects taking warfarin increased more than that in subjects taking PRADAXAReference:Pradaxa® (dabigatran etexilate mesylate) capsules [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; January 2012.
16Significant risk reduction of both ischemic stroke and hemorrhagic stroke vs warfarin Slide ID: 27052Significant risk reduction of ischemic stroke and hemorrhagic stroke vs warfarinThe contribution of the components of the composite primary endpoint, including stroke by subtype, is shown on this slide. The treatment effect was primarily a reduction in strokeThe risk of myocardial infarction was numerically greater in patients who received PRADAXA (1.5% for 150 mg dose) than in those who received warfarin (1.1%)Reference:Pradaxa® (dabigatran etexilate mesylate) capsules [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; January 2012.
17Higher rate of major GI bleeds (1.6% vs 1.1% for warfarin) Slide ID: 27054The number of total bleeds was lower in patients treated with PRADAXA 150 mg twice daily than with warfarin*This slide shows the number of patients experiencing bleeding events during RE-LYThe risk of major bleeding with PRADAXA 150 mg twice daily was similar to that of warfarin across major subgroups except age. There was a trend toward a higher incidence of major bleeding on PRADAXA (HR 1.2, 95% CI:1.0 to 1.4) for patients ≥ 75 years of ageHigher rate of major GI bleeds (1.6% vs 1.1% for warfarin)Similar rates of major bleeds (3.3% vs 3.6% for warfarin)Higher rate of total GI bleeds [681 (6.1%) vs 452 (4.0%) for warfarin]Lower rate of life-threatening bleeds (1.5% vs 1.9% for warfarin)Major bleeds fulfilled one or more of the following criteria:Bleeding associated with a reduction in hemoglobin of at least 2 grams per deciliter or leading to a transfusion of at least 2 units of bloodSymptomatic bleeding in a critical area or organ (intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding)A life-threatening bleed met one or more of the following criteria:FatalSymptomatic intracranial bleedReduction in hemoglobin of at least 5 grams per deciliterTransfusion of at least 4 units of bloodAssociated with hypotension requiring the use of intravenous inotropic agentsNecessitating surgical intervention*PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding.Reference:Pradaxa® (dabigatran etexilate mesylate) capsules [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; January 2012.
19Renal function should be assessed when selecting the dose of PRADAXA Slide ID: 27060Renal function should be assessed when selecting the dose of PRADAXARenal function should be assessed by calculating the creatinine clearance (CrCl) prior to initiation of treatment with PRADAXAIn the RE-LY trial, creatinine clearance was calculated using the Cockcroft-Gault formulaFor patients with creatinine clearance (CrCl) >30 mL/min, the recommended dose of PRADAXA is 150 mg taken orally, twice daily, with or without foodFor most patients, the recommended dose of PRADAXA is 150 mg twice dailyFor patients with severe renal impairment (CrCl mL/min), the recommended dose is 75 mg twice daily. Dosing recommendations in subjects with severe renal impairment are based on pharmacokinetic modelingDosing recommendations for patients with a CrCl <15 mL/min OR on dialysis cannot be providedReference:Pradaxa® (dabigatran etexilate mesylate) capsules [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; January 2012.
21Use of PRADAXA and surgical interventions Slide ID: 27063Use of PRADAXA and surgical interventionsIf possible, discontinue PRADAXA 1 to 2 days (CrCl ≥50 mL/min) or 3 to 5 days (CrCl <50 mL/min) before invasive or surgical procedures because of the increased risk of bleedingConsider longer times for patients undergoing major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, in whom complete hemostasis may be requiredIf surgery cannot be delayed, there is an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of interventionThe aPTT test provides an approximation of PRADAXA’s anticoagulant effectThe degree of anticoagulant activity can also be assessed by ECT. This test is a more specific measure of the effect of dabigatran than aPTTINR is relatively insensitive to the exposure to dabigatran and cannot be interpreted the same way as used for warfarin monitoringWhen necessary, use aPTT or ECT and not INR, to assess anticoagulant activity in patients on PRADAXAReference:Pradaxa® (dabigatran etexilate mesylate) capsules [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; January 2012.
22Managing anticoagulant effects of PRADAXA in cases of hemorrhagic complications Slide ID: 27065Managing anticoagulant effects of PRADAXA in cases of hemorrhagic complicationsThere is no reversal agent for dabigatran1In the event of hemorrhagic complications, initiate appropriate clinical support in accordance with standard medical practice. Consider the following1:Discontinue treatment with PRADAXAInvestigate the source of bleedingConsider transfusion of fresh frozen plasma or red blood cells2; consider administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs have been usedConsider initiation of dialysis, as approximately 60% of the drug can be removed over 2 to 3 hours. Data supporting this approach are limitedMeasurement of aPTT or ECT may help guide therapyAdditional considerations1:Use of activated prothrombin complex concentrates (aPCCs, e.g., FEIBA), recombinant Factor VIIa, or concentrates of coagulation factors II, IX, or XProtamine sulfate and vitamin K are not expected to affect the anticoagulant activity of dabigatranReference:Pradaxa® (dabigatran etexilate mesylate) capsules [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; January 2012.Cushman M, Lim W, Zakai NA; American Society of Hematology Clinical Practice Guide on Anticoagulant Dosing and Management of Anticoagulant-Associated Bleeding Complications in Adults [Quick Reference guide]. Washington, DC: American Society of Hematology; 2011.
23Rivaroxaban (Xarelto) G w_script.ppt4/13/2017 6:30:35 PMRivaroxaban (Xarelto)TF/VIIaDirect, specific, competitive factor Xa inhibitorHalf-life 5-13 hoursClearance :1/3 direct renal excretion2/3 metabolism via CYP 450 enzymesOral, once daily dosing with largest meal without need for coagulation monitoringXIXIXaVIIIaRivaroxabanVaXaIIIIaFibrinogenFibrinAdapted from Weitz et al, 2005; 2008
24Primary Efficacy Outcome Stroke and non-CNS Embolism RivaroxabanWarfarinEvent Rate1.712.16WarfarinRivaroxabanCumulative event rate (%)HR (95% CI): 0.79 (0.66, 0.96)P-value Non-Inferiority: <0.001Days from RandomizationNo. at risk:RivaroxabanWarfarinEvent Rates are per 100 patient-yearsBased on Protocol Compliant on Treatment Population
25Primary Safety Outcomes RivaroxabanWarfarinEvent RateHR (95% CI)P-valueMajor and non-major Clinically Relevant14.9114.521.03 (0.96, 1.11)0.442Major3.603.451.04 (0.90, 1.20)0.576Non-major Clinically Relevant11.8011.371.04 (0.96, 1.13)0.345Event Rates are per 100 patient-yearsBased on Safety on Treatment Population
26Bleeding Sites CrCl 30–49 ml/min CrCl ≥50 ml/min Riva 15 mg (N = 1474) Warfarin(N=1476)P-valueRiva 20 mg(N=5637)(N=5640)GI (upper, lower, and rectal)2.881.770.021.791.120.0002Intracranial0.710.880.540.44Macroscopic haematuria0.050.180.220.280.190.21Bleeding associated with non-cardiac surgery0.240.420.310.150.61Intra-articular0.000.230.990.170.98Epistaxis0.090.400.100.130.53*Major bleeding per 100 pt-yrs of follow-up
27Key Secondary Efficacy Outcomes RivaroxabanWarfarinEvent RateHR (95% CI)P-valueVascular Death, Stroke, Embolism4.514.810.94 (0.84, 1.05)0.265Stroke Type Hemorrhagic Ischemic Unknown Type0.261.620.150.441.640.140.58 (0.38, 0.89)0.99 (0.82, 1.201.05 (0.55, 2.01)0.0120.9160.871Non-CNS Embolism0.160.210.74 (0.42, 1.320.308Myocardial Infarction1.021.110.91 (0.72, 1.16)0.464All Cause Mortality Vascular Non-vascular Unknown Cause4.522.911.150.464.9126.96.36.1990.92 (0.82, 1.03)0.94 (0.81, 1.08)0.94 (0.75, 1.18)0.80 (0.57, 1.12)0.1520.3500.6110.195Event Rates are per 100 patient-yearsBased on Intention-to-Treat Population
28XARELTO® (rivaroxaban) Is Administered With Once-daily Dosing CrCl (mL/min)Recommended Once-daily Dose of XARELTO®>5020 mg15 to 5015 mg*<15Avoid useXARELTO® (rivaroxaban) should be administered as a once-daily dose of 20 mg with the evening meal in patients with CrCl>50 mL/minIn patients with CrCl of 15 to 50 mL/min, XARELTO® should be administered with the evening meal as a once-daily dose of 15 mgThese recommendations are based on the fact that the absolute bioavailability of XARELTO® is increased when taken with food. The evening meal is specified because that is how XARELTO® was given in the ROCKET AF trialPatients 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 functionXARELTO® should be avoided in patients with CrCl <15 mL/min. Periodically assess renal function as clinically indicated (eg, more frequently in situations in which renal function may decline) and adjust therapy accordinglyPatients who develop acute renal failure while on XARELTO® should discontinue treatmentIf a dose of XARELTO® is not taken at the scheduled time, administer the dose as soon as possible on the same dayXARELTO® should be taken once daily with the evening mealCoadministration 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.28
29XARELTO (rivaroxaban): Drug-Drug Interaction Profile Drugs (examples)PK/PD EffectsRecommendationCombined P-gp and strong CYP3A4 inhibitorsKetoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, conivaptanConcomitant use increases XARELTO exposure and PD effects; significant increases in rivaroxaban exposure may increase bleeding riskAvoid concomitant useCombined P-gp and strong CYP3A4 inducersCarbamazepine, phenytoin, rifampin, St. John’s wortConcomitant use decreases XARELTO exposure and PD effects, which may decrease efficacy of XARELTOAvoid concomitant use if these drugs must be coadministeredCombined 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, chloramphenicolBased 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/minUse only if potential benefit justifies riskXARELTO® (rivaroxaban) is a substrate of CYP3A4/5, CYP2J2, and the permeability- glycoprotein (P-gp) and adenosine triphosphate-binding cassette G2 (ABCG2) transporters. Inhibitors and inducers of these CYP450 enzymes or transporters may alter XARELTO® exposureAs significant increases in XARELTO® exposure may result in increased risk of bleeding, concomitant administration of XARELTO® with combined P-gp and strong cytochrome P450 3A4 (CYP3A4) inhibitors should be avoided. Coadministration of XARELTO® with a combined P-gp and strong CYP3A4 inducer could decrease exposure to, and potentially the efficacy of, XARELTO®. Therefore, the concomitant use of XARELTO® with drugs that are combined P-gp and strong CYP3A4 inducers should be avoidedSimulated pharmacokinetic data suggest that patients with renal impairment receiving a full dose of XARELTO® in combination with combined P-gp and weak or moderate CYP3A4 inhibitors may have increased exposure to XARELTO®ROCKET AF, however, allowed concomitant use of XARELTO® with such drugs, with no increase in bleeding seen in an analysis of patients with moderate renal impairment (CrCl of 30 to <50 mL/min) receiving XARELTO® with a concomitant combined P-gp and weak or moderate CYP3A4 inhibitorNevertheless, the XARELTO® Prescribing Information indicates that XARELTO® should be used in patients with CrCl of 15 to 50 mL/min who are receiving concomitant combined P-gp and weak/moderate CYP3A4 inhibitors only if the potential benefit justifies the potential riskAbbreviations: CYP = cytochrome P450; PK/PD = pharmacokinetic/pharmacodynamic.2929
30Interrupting 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 procedureIn 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 interventionXARELTO® should be restarted after the surgical or other procedures as soon as adequate hemostasis has been establishedIf oral medication cannot be taken after surgical intervention, consider a parenteral anticoagulantWait at least 18 hours after last dose before removal of epidural catheter, and do not restart until at least 6 hours after removal.This slide reviews guidance on interrupting XARELTO® (rivaroxaban) for patients who undergo surgical proceduresIf anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, then XARELTO® should be stopped at least 24 hours before the procedureIn 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 the interventionXARELTO® should be restarted after surgical or other procedures as soon as adequate hemostasis has been established. If oral medication cannot be taken after surgical intervention, consider administering a parenteral anticoagulant
31Considerations for Managing Bleeding in Patients Receiving XARELTO® (rivaroxaban) A specific antidote for XARELTO® is not availableXARELTO® is not expected to be dialyzable due to high plasma-protein bindingProtamine 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 trialsThere 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®There are several considerations for managing bleeding in patients receiving XARELTO® (rivaroxaban)A specific antidote for XARELTO® is not availableNotably, XARELTO® is not expected to be dialyzable due to high-plasma protein bindingAdditionally, protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of XARELTO®Use of procoagulant reversal agents, eg, prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trialsThere is no experience with antifibrinolytic agents, such as tranexamic acid or aminocaproic acid, in individuals receiving XARELTO®Additionally, there is neither scientific rationale for benefit nor experience with systemic hemostatics, such as desmopressin and aprotinin, in individuals receiving XARELTO®Abbreviations: APCC = activated prothrombin complex concentrate; PCC = prothrombin complex concentrate; rFVIIa = recombinant factor VIIa.
32Apixaban (ELIQUIS) TF/VIIa Xa IIa G w_script.ppt4/13/2017 6:30:35 PMApixaban (ELIQUIS)TF/VIIaDirect, specific, competitive factor Xa inhibitorHalf-life 12 hoursClearance :27% direct renal excretionBiliary and direct intestinal excretionP-gp transportOral, twice daily dosing without need for coagulation monitoring: 5mg bid. 2.5mg bid with at least 2 of: 80 or older, weight <60kg, creatinine >1.5XIXIXaVIIIaApixabanVaXaIIIIaFibrinogenFibrin
33Granger CB et al. N Engl J Med 2011;365:981-992. Kaplan–Meier Curves for the Primary Efficacy and Safety Outcomes.Figure 1. Kaplan–Meier Curves for the Primary Efficacy and Safety Outcomes. The primary efficacy outcome (Panel A) was stroke or systemic embolism. The primary safety outcome (Panel B) was major bleeding, as defined according to the criteria of the International Society on Thrombosis and Haemostasis. The inset in each panel shows the same data on an enlarged segment of the y axis.Granger CB et al. N Engl J Med 2011;365:
34Granger 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:
35APIXABAN 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.
36APIXABANELIQUIS 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.
37FDA 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.
38PradaxaXareltoEliquis150mg bid Cr.Cl >3075mg bid Cr.Cl 15-30Avoid Cr.Cl <1520mg Cr.Cl >5015mg Cr.Cl 15-505mg bid2.5mg bid if 2 or more:>80, <60kg, >creat 1.5With or without foodLargest mealAvoid 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 levelsAvoid 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 15-50Avoid rifampin, carbamazepine, phenytoin, St. John’s wart. Reduce to 2.5mg bid with ketoconazole, itraconazole, Biaxan. If on 2.5mg bid, stop Eliquis.
39PRADAXAXARELTOELIQUISConverting from warfarin: start when INR<2Converting from warfarin: start when INR<3Rapid onsetNo monitoring(PTT)(INR, PTT, anti-factor Xa activity)1-2 day hold if Cr.Cl >503-5 if Cr.Cl <50At least 24 hoursAt least 24 hours low riskAt least 48 hours high riskBaseline Cr.Cl , at least 6 monthlyBaseline Cr.Cl, at least 6 monthlyExtreme caution with epidural cathetersCannot crushCan crush (apple sauce)
40PRADAXAXARELTOELIQUISDVT, PE, extendedHip and knee prophylaxis