Target-Specific Oral Anticoagulants: A review for cardiovascular practitioners

Transcription

1 Target-Specific Oral Anticoagulants: A review for cardiovascular practitioners Beena Cheriyan, PharmD Clinical Pharmacy Specialist Cardiology St. Joseph Mercy Hospital Ann Arbor February 19th, 2015

2 2 Disclosure Statement I have no financial disclosures or conflict of interests related to this topic. No sponsorship, commercial support, endorsement of products will occur during this presentation.

3 3 Objectives Discuss the FDA indication for new oral anticoagulants Identify important contraindications related to new agents Discuss how to manage patients on new oral anticoagulants in the hospital

4 INFONET RESOURCES 4

5 Departments Inpatient Pharmacy Coag Management 5

6 b 6

7 7 Target-Specific Oral Anticoagulants: Background

8 8 Drug class name change! Changed from Novel Oral Anticoagulants (NOAC) to Target-Specific Oral Anticoagulants (TSOA) Nothing stays young forever! Errors associated with the old nomenclature

9 9 Atrial Fibrillation Prevalence Prevalence is ~1-2% Expected to rise by 5-fold by 2050 Associated with a 5-fold increase in strokes

10 10 Assess Clot vs. Bleed Risk 0pt: 1.1% 1pt: 1.1% 2pt: 1.9% 3pts: 3.7% 4pt: 8.7% 5pts: 12.5% >5pt: no data

11 11 Timeline of current OA s dabigatran 2010 rivaroxaban 2011 Warfarin 1953 Ximelagatran 2004 apixaban 2012 edoxaban s 1960s 1970s

12 PROS CONS 12 LESS drug interactions than warfarin No lab monitoring Convenient - compliance may be improved No bridging!! More predictable No dietary restrictions THERE ARE STILL IMPORTANT DRUG INTERACTIONS!! No reversal agents! Not approved in valvular disease Not cheap! Insurance Coverage? Renal/hepatic concerns??obese or underweight patients Dabigatran and apixaban are twice daily Increased risk of stroke if stopped for >48hr! No comparative trials

13 13 What is non-valvular AFib? 2014 AHA/ACC/HRS AFib guidelines Defines nonvalvular AFib as AFib in the absence of Rheumatic mitral stenosis Mechanical or bioprosthetic heart valve Mitral valve repair The following were EXCLUDED in the three major TSOA trials (RELY, ARISTOTLE, ROCKET-AF) Mechanical heart valve Moderate to severe mitral stenosis Moderate to severe aortic stenosis

14 14 MAJOR Contraindication DO NOT USE IN PATIENTS WITH MECHANICAL HEART VALVES Phase 3 Trial REALIGN (Dabigatran vs. warfarin in Heart Valve patients with AFib) was STOPPED EARLY due to increased strokes, MI, valve thrombus Studies with rivaroxaban and apixaban are lacking AVOID!! USE WARFARIN!!! (Class 1B)

15 TSOA drug information 15

16 The TSOA s 16

17 Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) 17 Trials RELY ROCKET AF ARISTOTLE Safety/ Efficacy compared to warfarin -150mg Q12h dose was superior to warfarin in reducing stroke and systemic embolism. -Similar risk of major bleeding and all-cause mortality. -Dose of 75mg q12h was not studied. -Non-inferior to warfarin in stroke and systemic embolism risk reduction. -A similar incidence of major bleeding to warfarin therapy. -Reported a statistically significant reduction in stroke and systemic embolism risk, major bleeding, and all-cause mortality compared to warfarin. Stroke YES (34%) NONINFERIOR YES (20%) ICH YES YES YES death YES YES YES Bleeding GI GI Any cause BC 5.13

18 18 Oral Anticoagulant Mechanism of Action Intrinsic system (surface contact) Warfarin Extrinsic system (tissue damage) Warfarin: Factors II, VII, IX, X, S, C Factor VII:6 hr Protein C: 21hr Factor IX: 24 hr Factor X: 40 hr Protein S: 43hr Factor II: 60 hr Factor Xa Inhibitor Factor Xa Inhibitor Apixaban Rivaroxaban Fondaparinux Edoxaban* Direct Thrombin Inhibitor Argatroban, Dabigatran bivalirudin, Lepirudin Adapted from Hirsch et al. Blood 2005;105: and

19 Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Warfarin (Coumadin ) 19 Mech. of action Direct IIa inhibitor Xa inhibitor Xa inhibitor II, VII, IX, X, proteins C&S Onset Quick (1-2h) Quick (2-4h peak) Quick (3-4h peak) Delayed (5-7 days) Bioavail. 3 7% 66%, 50% 100% (w/ or without food) (increases w/food) (w/ or without food) Metabolism Converted to active drug by hydrolysis CYP3A4/5, CYP2J2 & hydrolysis Primarily CYP3A4/5 Primarily CYP2C9 Not via CYP P450 Renal clearance 80% (unchanged) 33% 25% 92% Hepatic Imp. N/A Avoid Child-Pugh B and C Avoid Child-Pugh C Avoid in severe disease Half life CrCl>80ml/min 13.8h; CrCl h; CrCl hr; CrCl< hr hr hr hr (Cpss: 5-7 d) Factor VII:6 hr; Protein C: 21hr Factor IX: 24 hr; Factor X: 40 hr Protein S: 42.5 hr Factor II: 60 hr BC 5.13

20 20 Case 1 AJ is a patient with AFib who is suffering from dysphagia after a prolonged intubation in the CCU. An NG tube has been placed and he will be starting PO medication. It is determined that the TSOA agents are appropriate for him. Which product can be crushed? A. Dabigatran only B. Rivaroxaban only C. Apixaban only D. Warfarin only E. Rivaroxaban, apixaban, warfarin, but not dabigatran

21 21 Dabigatran, rivaroxaban, apixaban. Oh my! Dabigatran: **DO NOT OPEN CAPSULES or CRUSH** Should never be removed from original packaging, as this will reduce its effectiveness. Rivaroxaban: GIVE WITH FOOD Can be crushed Not affected by extreme weights, but wt<50 had a 24% increase in Cmax Apixaban: Can be crushed Concerns with extreme wt: Wt>120kg had a 30% reduced exposure Wt<50kg 30% increased exposure Concern with elderly Age>80 had a 32% increase in exposure

22 22 Case 1 AJ is a patient with AFib who is suffering from dysphagia after a prolonged intubation in the CCU. An NG tube has been placed and he will be starting PO medication. It is determined that the TSOA agents are appropriate for him. Which product can be crushed? A. Dabigatran only B. Rivaroxaban only C. Apixaban only D. Warfarin only E. Rivaroxaban, apixaban, warfarin, but not dabigatran

23 Ind. Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) 23 Nonvalvular AF 150mg q12h (CrCl>30ml/min) 75mg q12h* (CrCl15-30) HD/CrCl<15 =AVOID 20mg daily (CrCl>50ml/min) 15mg daily (15-50 ml/min) HD/CrCl <15 = Avoid 5mg q12h 2.5mg q12h - Meet 2: Scr> 1.5 or wt < 60kg, or age >80 HD/CrCl<15 = Avoid* Valv. AF Not approved by FDA Not approved by FDA Not approved by FDA PE treatment 150mg Q12h Not approved at SJMH 15mg Q12h x 21d then, 20mg daily Avoid CrCl<30ml/min (non-inferior) 10mg Q12h x7d, then 5mg Q12h Avoid CrCl<30ml/min TKA/ THA prophy Not approved by FDA or SJMH (off label mg once daily) 10mg daily Avoid CrCl<30ml/min Not approved by FDA

24 24 Apixaban in ESRD *FDA approved apixaban dosing in ESRD pts who are stable on HD.* *Apixaban in ESRD is NOT APPROVED AT SJMH!* WHY??? No clinical evidence for safety and efficacy FDA approved dosing based on pharmacokinetic modeling! Warfarin is still consider acceptable if warranted If on at home, there must be a discussion between cardiologist/nephrologist discussion management in hospital

25 Drug Interactions: They do exist! 25

26 26 CASE 2 75 yo M presents with new onset Afib. PMH HTN, seizures, D-HF, HL Meds: metoprolol 100 XL daily, lisinopril 10mg daily, phenytoin 150mg Q12h, simva 20mg HS, itraconazole 100mg TID, St. John s Wort Scr admission = CrCl =58ml/min. Hgb 15.1 What do you do with his anticoagulants? A. Start apixaban 5mg q12h B. Start dabigatran 150mg Q12h today. It has the least number of drug interactions C. Start Xarelto and bridge with heparin gtt until INR is therapeutic D. Start warfarin. There is a major interaction with phenytoin, itraconazole, St John s Wort with all TSOAs.

27 TSOA Drug Interactions 27 Dabigatran Rivaroxaban Apixaban AVOID Ketaconazole Itraconazole Voriconazole Posaconazole Lopinavir/ritonavir Cyclosporine Tacrolimus Rifampin St John s Wort Carbamazepine Phenytoin Ketaconazole m Itraconazole m HIV protease inh. L (iopinavir, ritonavir, indinavir) m Dronedarone L Conivaptan m Carbamazepine m Phenytoin m Rifampin m St John s Wort m Ketaconazole Itraconazole Voriconazole posaconazole HIV protease inh. Lopinavir/ritonavir Rifampin St John s Wort Phenytoin Carbamazepine Reduce or Avoid Verapamil Amio/quinidine/clarithro/ phenobarb Dronedarone m CrCl15-50ml/min: m Verapamil Erythromycin Diltiazem Felodipine Azithro Amio Diltiazem Clarithromycin* Conivaptan*

28 28 CASE 2 75 yo M presents with new onset AFib. PMH HTN, seizures, D-HF, HL Meds: metoprolol 100 XL daily, lisinopril 10mg daily, phenytoin 150mg Q12h, simva 20mg HS, itraconazole 100mg TID, St. John s Wort Scr (B/L) = 0.98 Scr admission = CrCl =58ml/min What do you do with his anticoagulants? A. Start apixaban 5mg q12h B. Start dabigatran 150mg Q12h today. It has the least number of drug interactions C. Start rivaroxaban and bridge with heparin gtt until INR is therapeutic D. Start warfarin. There is a major interaction with phenytoin, itraconazole and St. John s Wort with all TSOAs.

29 29 CASE 3 86 yo M presents from a NH with atypical CP x3 days, and is severely demented. He rules in for a NSTEMI and it is decided he will undergo medical management. PMH AFib, HTN, dementia, BPH NH Meds: Coreg 25mg Q12h, Flecainide 100mg q12h, rivaroxaban 20mg w/dinner (last dose was last night), flomax 0.4mg QD, Aricept 10mg QD, simva 20mg HS Scr admission = 1.50 (baseline = 0.8). CrCl =40ml/min. Hgb 14.0, Plt 248 Trop - 1.0

30 30 CASE 3 For NSTEMI medical management Dr Watson orders ASA 81mg, coreg 25mg Q12h, atorvastatin 40mg. He also enters an order for Xarelto to start tonight, and a heparin gtt to start now. In the comments he says to continue both agents together. What do you do? A. Continue rivaroxaban for AFib treatment, AND add heparin gtt for NSTEMI treatment B. Call intern and state rivaroxaban is all that is needed for treatment of his AFib and NSTEMI C. Call the intern and ask him to d/c rivaroxaban, and continue heparin when next rivaroxaban dose would have been due (tonight at 1700) to treat NSTEMI x48h. Then restart rivaroxaban when Scr is back to baseline and pt is off heparin.

31 31 CASE 3 For NSTEMI medical management Dr Watson orders ASA 81mg, coreg 25mg Q12h, atorvastatin 40mg. He also enters an order for Xarelto to start tonight, and a heparin gtt to start now. In the comments he says to continue both agents together. What do you do? A. Continue rivaroxaban for AFib treatment, AND add heparin gtt for NSTEMI treatment B. Call intern and state rivaroxaban is all that is needed for treatment of his AFib and NSTEMI C. Call the intern and ask him to d/c rivaroxaban, and continue heparin when next rivaroxaban dose would have been due (tonight at 1700) to treat NSTEMI x48h. Then restart rivaroxaban when Scr is back to baseline and pt is off heparin.

32 Discontinue heparin and start lovenox 1 hr later 32

33 33 Converting from UFH/LMWH to TSOA Discontinue UFH and start TSOA immediately Start TSOA when next dose of LMWH would be due, and discontinue LMWH. DO NOT bridge TSOAs with UFH/LMWH!!! DO NOT use TSOAs as a bridge to warfarin!

34 34 Converting from TSOA to UFH Start heparin when next dose of TSOA would be due Bolus not recommended, but clinical decision is required

35 35 Surgical Interventions Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Warfarin (Coumadin ) D/c for surgery/ intervention CrCl> days prior to CrCl<50 3 to 5 days prior to Moderate/high 48-72hr Low risk -24hr prior to procedure Moderate/high >48h prior to Low risk > 24h prior to Mod/high - INR <1.3 Low risk - INR <1.6 Dabigatran half life: CrCl>80ml/min 13.8h; CrCl h; CrCl hr; CrCl< hr Radial approach is recommended in PCI Outweight risk of bleeding vs. risk of not doing the intervention BC 5.13

36 36 Reversal? Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Warfarin (Coumadin ) Reversal *No antidote *No antidote *No antidote Vitamin K PCC4 considered (No evidence) Consider HD Activated charcoal 2 to 6 hours after ingestion Consider activated charcoal for overdose PCC4 Not dialyzable Not dialyzable Activated charcoal for overdose FFP **Prothrombin Concentrate (PCC4) - II, VII, IX, X, Protein C&S - Only for EMERGENT BC 5.13

37 37 Who is a good candidate? Non-valvular Afib Good compliance history History of unstable INRs with good compliance on warfarin Understands risk of no reversal agent Accurate home med list WITH NO CONTRAINDICTED DRUGS Good insurance coverage Good hepatic and renal fxn Not actively bleeding

38 38

39 References Cabral KP. Pharmacology of the new target specific oral anticoagulants. J Thromb Thrombolysis (2013) 36: Granger CB et al (2011) Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365: Smith SC Jr., Feldman TE, Hirshfeld JW Jr., et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention summary article: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2006; 47: Alexander JH, Lopes RD, James S, et al., for the APPRAISE-2 Investigators. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011;365: Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361: Patel MR, et al. Rivaroxaban vs. warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365: Eikelboom JW, et al. New Anticoagulants. Circulation, 2010;121: European heart rhythm association practical guide on the use of new oral anticoagulants in patients with nonvalvular atrial fibrillation. Europace(2013) 15: ACC/AHA/ESC guidelines for management of patient with atrial fibrillation: executive summary. Circulation 2001; 104: Dewilde WJ, et al. Triple therapy for atrial fibrillation and percutaneous coronary intervention. J AM Coll Cardio 2014;64: Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; URL: Updated Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; URL: Updated Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; URL: Updated

40 The natural cure for atrial fibrillation.. 40