ORAL ANTICOAGULANTS IN THE 21ST CENTURY: A PRACTICAL GUIDE TO USING NEWER AGENTS Katherine Vogel Anderson, Pharm.D., BCACP University of Florida Colleges of Pharmacy and Medicine Disclosures I have nothing to disclose Case BV is a 75 year old white male who has just been diagnosed with a. fib. His past medical history is significant for hypertension (taking chlorthalidone) and seasonal allergies. Which oral anticoagulant do you recommend? A. Apixaban B. Dabigatran C. Rivaroxaban D. Warfarin Objectives Identify new oral anticoagulants (OACs) Determine the current place in therapy for OACs Review appropriate transitions between parenteral anticoagulants and OACs (and vice versa) Highlight pharmacotherapy scenarios when changing between OACs Identify OAC options peri-procedure A History Lesson… 1930s heparin 1950s warfarin 1990s LMWH 2001 fondaparinux 2010 dabigatran 2011 rivaroxaban 2012 apixaban 2013… What do I choose? *All are FDA approved for stroke prevention secondary to a. fib warfarin rivaroxaban and apixaban dabigatran FDA-Approved Doses Mechanism Apixaban Dabigatran Rivaroxaban Warfarin Activated factor Xa inhibitor Direct thrombin inhbitor Activated factor Xa inhibitor Vitamin K antagonist Dose for stroke prevention secondary to a. fib 5mg twice daily 150mg twice daily 20mg once daily Renal dose adjustment 2.5mg twice daily 75mg twice daily 15mg once daily Dosed to achieve an INR between 2 and 3 Not required Also approved for VTE treatment and prevention If it isn’t broken, why fix it? What’s wrong with warfarin? Monthly monitoring Drug interactions Takes lots of time… New OACs BUT new OACs… • Don’t require monitoring • Fewer interactions • Quicker onset of action • Lack antidotes • Require renal adjustment • Are expensive In a nutshell… Katsnelson M et al. Circulation 2012;125: 1577-1583 A wise man once said… “Inferiors revolt in order that they may be equal, and equals that they may be superior. Such is the state of mind, which creates revolutions.” —Aristotle. In: Politics. Book V; Part II; 350 B.C.E. Nedeltchev K. Stroke 2012;43: 922-923 Back to our case… Which oral anticoagulant do you recommend? A. Apixaban B. Dabigatran C. Rivaroxaban D. Warfarin Warfarin Pharmacogenomic dosing? Regardless – treat to an INR between 2 and 3 You JJ et al. Chest 2012;141(2)(Suppl): e531S-e575S Coumadin (warfarin) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2011 Oct. But… Which oral anticoagulant do you recommend? A. Apixaban B. Dabigatran C. Rivaroxaban D. Warfarin Prodrug? Yes Food? No effect Drug interactions P-gp substrate: Verapamil decrease dabigatran dose Dronedarone decrease/don’t use Renal adjustment CrCL < 30ml/min 75mg twice daily Pros the oldest of the new Cons GI intolerance; renal dose not prospectively studied Heidbuchel H et al. Europace 2013;15: 625-651 But… Which oral anticoagulant do you recommend? A. Apixaban B. Dabigatran C. Rivaroxaban D. Warfarin Prodrug? No Food? Mandatory Drug interactions P-gp AND CYP3A4 substrate: Amiodarone, diltiazem, verapamil – caution if CrCL is less than 50ml/min AVOID with strong inhibitors Renal adjustment CrCL 15 – 50ml/min 15mg once daily Pros once daily dosing; renal adjustments Cons once daily dosing; food requirement Heidbuchel H et al. Europace 2013;15: 625-651 But… Which oral anticoagulant do you recommend? A. Apixaban B. Dabigatran C. Rivaroxaban D. Warfarin Prodrug? No Food? No effect Drug interactions CYP3A4 substrate: Reduce dose to 2.5mg/avoid with strong CYP3A4 and P-gp inhibitors Renal adjustment If SCr is greater than 1.5mg/dl, patient is greater than 80 years old, patient weighs less than 60Kg 2.5mg twice daily Pros renal dose prospectively studied Cons twice daily dosing; newest of the new Heidbuchel H et al. Europace 2013;15: 625-651 Some considerations Although new OACs are substrates for P-gp and CYP, they are not inhibitors PPI use does not have a clinical effect on efficacy Bleeding risk increases with antiplatelet agents Compliance is key effectiveness fades fast 12 – 24 hours after last dose = no anticoagulation The decision is made... … A new OAC will be prescribed for BV So – what’s next? Do we really NOT monitor? What if BV has a procedure? What if BV wants to switch to warfarin? Let’s get started… Heidbuchel H et al. Europace 2013;15: 625-651 Patient anticoagulation cards: www.noacforaf.eu PPI: No prospective evidence, but consider a PPI for high risk patients (i.e. history of GI bleed) Follow up visits: Compliance S/Sx thromboembolism and/or bleeding Side effects Medication reconciliation Labs: 3, 6, 12 months and as needed Heidbuchel H et al. Europace 2013;15: 625-651 Coagulation Monitoring Dabigatran Apixaban Rivaroxaban Plasma peak (after ingestion) 2 hours 1 – 4 hours 2 – 4 hours Plasma trough (after ingestion) 12 – 24 hours 12 – 24 hours 16 – 24 hours PT N/A N/A Prolonged INR Increase Increase Increase aPTT >2xULN @ trough N/A suggests risk N/A Anti-Xa N/A Quantitative ECT >3xULN @ trough N/A suggests risk Heidbuchel H et al. Europace 2013;15: 625-651 No data YET N/A Transitions in Therapy To a new OAC… heparin upon discontinuation (~2 hours) From low molecular weight heparin (LMWH) when the next dose of LMWH is due From From a new OAC… To warfarin similar to “bridging” The new OAC is taken simultaneously with warfarin until the INR is within the appropriate therapeutic range To LMWH when the next dose of OAC is due Heidbuchel H et al. Europace 2013;15: 625-651 Transitions in Therapy From warfarin to a new OAC: As soon as the INR is less than 2 If INR is between 2 and 2.5 start the next day For INR greater than 2.5 It depends How high is the INR? Wait and hold Draw a new INR If INR is less than 2.5, proceed as above Heidbuchel H et al. Europace 2013;15: 625-651 Peri-procedural management of OAC When do you stop the new OAC? Evaluate Patient factors = age, renal function, history of bleeding AND Procedure factors No bleeding risk Minor bleeding risk Major bleeding risk No need to hold the OAC Heidbuchel H et al. Europace 2013;15: 625-651 Peri-procedural management of OAC Hold the OAC 24 hours prior Hold the OAC 48 hours prior Resume OAC 6 – 8 hours after the procedure IF immediate and complete hemostasis is achieved AND re-bleeding risk is minimal. If invasive procedure, resumption of OAC may be deferred for 48 - 72 hours Heidbuchel H et al. Europace 2013;15: 625-651 Management of bleeding Heidbuchel H et al. Europace 2013;15: 625-651 Two Clinical Questions What about aspirin? Post-ACS: ASA or clopidogrel + new OAC = increased bleeding apixaban or rivaroxaban may be preferred Within the first year ASA + decreased OAC dose After the first year OAC alone What about valves? NOT for valvular atrial fibrillation NOT for mechanical valve replacement Heidbuchel H et al. Europace 2013;15: 625-651 Back to our case… Which oral anticoagulant do you recommend? A. Apixaban B. Dabigatran C. Rivaroxaban D. Warfarin My answer I’m old school… But, if pressed to choose a new one…. Thanks for your attention!