MANAGEMENT OF ANTICOAGULATION FOR ATRIAL FIBRILLATION 2014 CONFIRM ATRIAL FIBRILLATION/FLUTTER DETERMINE STROKE RISK CHOOSE ANTICOAGULANT AGENT, WITH ASSESSMENT OF BLEEDING RISK DRUG INTERACTIONS, ANTIPLATELET AGENTS.

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

Stroke risk was equivalent with intermittent and sustained NVAF in SPAF trials1 Slide ID: 27040 Stroke risk is equivalent with intermittent and sustained NVAF In 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 participants This 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 stroke Reference: 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;35:183-187.

CHADS2 Risk Score and Corresponding Risk for Stroke in AF Patients Not Treated With Anticoagulant Therapy Points Annual Stroke Risk 95% Confidence Interval 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

CHA2DS2-VASc Congestive heart failure 1 Hypertension 1 Age > 75 2 Diabetes 1 Stroke/TIA/TE 2 Vascular disease (MI, PAD, aortic plaque) 1 Age 65-74 1 Female sex 1

CHA2DS2-VASc Stroke rate %/year 0% 1 1.3% 2 2.2% 3 3.2% 4 4.0% 5 6.7% 6 9.8% 7 9.6% 8 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

HAS-BLED Clinically Relevant Bleeding Major Bleeding 7% 1% 1 8% 2 11% 7% 1% 1 8% 2 11% 2% 3 16% 3% 4 15% >5 38%

HAS-BLED CHADS2 Clinically Relevant Bleeding Major Bleeding 7% 1% 1 8% 7% 1% 1 8% 2 11% 2% 3 16% 3% 4 15% >5 38% Points Annual Stroke Risk 95% Confidence Interval 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

Score Risk Anticoagulation Considerations 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) or dabigatran (Pradaxa) or rivaroxaban (Xarelto) or apixaban (Eliquis)

Pradaxa (dabigatran) TF/VIIa Xa IIa G02-536 w_script.ppt 4/13/2017 6:30:35 PM Pradaxa (dabigatran) TF/VIIa 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 X IX IXa VIIIa Va Xa II Dabigatran IIa Fibrinogen Fibrin Adapted from Weitz et al, 2005; 2008

PRADAXA 150 mg twice daily was significant in reducing the risk of stroke and systemic embolism an additional 35% vs warfarin PRADAXA= DABIGATRAN Slide ID: 27051 PRADAXA 150 mg twice daily was significant in reducing the risk of stroke and systemic embolism vs warfarin Effects of PRADAXA compared to warfarin were more apparent in patients with lower levels of INR control The 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 PRADAXA Reference: Pradaxa® (dabigatran etexilate mesylate) capsules [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; January 2012.

Significant risk reduction of both ischemic stroke and hemorrhagic stroke vs warfarin Slide ID: 27052 Significant risk reduction of ischemic stroke and hemorrhagic stroke vs warfarin The 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 stroke The 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.

Higher rate of major GI bleeds (1.6% vs 1.1% for warfarin) Slide ID: 27054 The 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-LY The 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 age Higher 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 blood Symptomatic 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: Fatal Symptomatic intracranial bleed Reduction in hemoglobin of at least 5 grams per deciliter Transfusion of at least 4 units of blood Associated with hypotension requiring the use of intravenous inotropic agents Necessitating 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.

Renal function should be assessed when selecting the dose of PRADAXA Slide ID: 27060 Renal function should be assessed when selecting the dose of PRADAXA Renal function should be assessed by calculating the creatinine clearance (CrCl) prior to initiation of treatment with PRADAXA In the RE-LY trial, creatinine clearance was calculated using the Cockcroft-Gault formula For patients with creatinine clearance (CrCl) >30 mL/min, the recommended dose of PRADAXA is 150 mg taken orally, twice daily, with or without food For most patients, the recommended dose of PRADAXA is 150 mg twice daily For patients with severe renal impairment (CrCl 15-30 mL/min), the recommended dose is 75 mg twice daily. Dosing recommendations in subjects with severe renal impairment are based on pharmacokinetic modeling Dosing recommendations for patients with a CrCl <15 mL/min OR on dialysis cannot be provided Reference: Pradaxa® (dabigatran etexilate mesylate) capsules [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; January 2012.

Use of PRADAXA and surgical interventions Slide ID: 27063 Use of PRADAXA and surgical interventions If 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 bleeding Consider 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 required If surgery cannot be delayed, there is an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention The aPTT test provides an approximation of PRADAXA’s anticoagulant effect The degree of anticoagulant activity can also be assessed by ECT. This test is a more specific measure of the effect of dabigatran than aPTT INR is relatively insensitive to the exposure to dabigatran and cannot be interpreted the same way as used for warfarin monitoring When necessary, use aPTT or ECT and not INR, to assess anticoagulant activity in patients on PRADAXA Reference: Pradaxa® (dabigatran etexilate mesylate) capsules [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; January 2012.

Managing anticoagulant effects of PRADAXA in cases of hemorrhagic complications Slide ID: 27065 Managing anticoagulant effects of PRADAXA in cases of hemorrhagic complications There is no reversal agent for dabigatran1 In the event of hemorrhagic complications, initiate appropriate clinical support in accordance with standard medical practice. Consider the following1: Discontinue treatment with PRADAXA Investigate the source of bleeding Consider 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 used Consider initiation of dialysis, as approximately 60% of the drug can be removed over 2 to 3 hours. Data supporting this approach are limited Measurement of aPTT or ECT may help guide therapy Additional considerations1: Use of activated prothrombin complex concentrates (aPCCs, e.g., FEIBA), recombinant Factor VIIa, or concentrates of coagulation factors II, IX, or X Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of dabigatran Reference: 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. 2011 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.

Rivaroxaban (Xarelto) G02-536 w_script.ppt 4/13/2017 6:30:35 PM Rivaroxaban (Xarelto) TF/VIIa 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 X IX IXa VIIIa Rivaroxaban Va Xa II IIa Fibrinogen Fibrin Adapted from Weitz et al, 2005; 2008

Primary Efficacy Outcome Stroke and non-CNS Embolism Rivaroxaban Warfarin Event Rate 1.71 2.16 Warfarin Rivaroxaban Cumulative event rate (%) HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001 Days from Randomization No. at risk: Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634 Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655 Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population

Primary Safety Outcomes Rivaroxaban Warfarin 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-years Based 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) (N=5640) 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 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 0.61 Intra-articular 0.00 0.23 0.99 0.17 0.98 Epistaxis 0.09 0.40 0.10 0.13 0.53 *Major bleeding per 100 pt-yrs of follow-up

Key Secondary Efficacy Outcomes Rivaroxaban Warfarin 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 0.26 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 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 4.52 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 Event Rates are per 100 patient-years Based on Intention-to-Treat Population

XARELTO® (rivaroxaban) Is Administered With Once-daily Dosing CrCl (mL/min) Recommended Once-daily Dose of XARELTO® >50 20 mg 15 to 50 15 mg* <15 Avoid use XARELTO® (rivaroxaban) should be administered as a once-daily dose of 20 mg with the evening meal in patients with CrCl>50 mL/min In patients with CrCl of 15 to 50 mL/min, XARELTO® should be administered with the evening meal as a once-daily dose of 15 mg These 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 trial 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 XARELTO® 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 accordingly Patients who develop acute renal failure while on XARELTO® should discontinue treatment If a dose of XARELTO® is not taken at the scheduled time, administer the dose as soon as possible on the same day 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. 28

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 XARELTO® (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® exposure As 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 avoided Simulated 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 inhibitor Nevertheless, 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 risk Abbreviations: CYP = cytochrome P450; PK/PD = pharmacokinetic/pharmacodynamic. 29 29

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. This slide reviews guidance on interrupting XARELTO® (rivaroxaban) for patients who undergo surgical procedures If 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 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 the intervention XARELTO® 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

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® There are several considerations for managing bleeding in patients receiving XARELTO® (rivaroxaban) A specific antidote for XARELTO® is not available Notably, XARELTO® is not expected to be dialyzable due to high-plasma protein binding Additionally, 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 trials There 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.

Apixaban (ELIQUIS) TF/VIIa Xa IIa G02-536 w_script.ppt 4/13/2017 6:30:35 PM Apixaban (ELIQUIS) TF/VIIa 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 X IX IXa VIIIa Apixaban Va Xa II IIa Fibrinogen Fibrin

Granger 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;365:981-992.

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 >30 75mg bid Cr.Cl 15-30 Avoid Cr.Cl <15 20mg Cr.Cl >50 15mg Cr.Cl 15-50 5mg bid 2.5mg bid if 2 or more: >80, <60kg, >creat 1.5 With or without food Largest meal 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.

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

PRADAXA XARELTO ELIQUIS DVT, PE, extended Hip and knee prophylaxis