Comparative Anticoagulation Laurajo Ryan, PharmD, MSc, BCPS, CDE Clinical Associate Professor The University of Texas at Austin College of Pharmacy The University of Texas Health Science Center Pharmacotherapy Education Research Center Department of Medicine ryanl@uthscsa.edu
Learning Objectives Compare & contrast anticoagulant agents Indications, dosing, drug/food interactions & lab/monitoring parameters Identify when to switch from warfarin to a new anticoagulant & vice versa How to manage the transition
Thromboembolisms: The Problem United States Precise numbers unknown Estimated at 300-600K/year 1-2/1000 1/100 >80 YOA Mortality 60 100K/year 25% of patients with PE present with sudden death ½ with DVT Long-term complications 10 years ~33% recurrence CDC: http://www.cdc.gov/ncbddd/dvt/data.html
Anticoagulants Warfarin (Coumadin ) Inhibits clotting factors Heparins II, VII, IX, X Proteins C & S Unfractionated (UFH) Factor IIa Xa Low Molecular Weight (LMWH) Factor Xa >>> IIa Direct thrombin inhibitors Lepirudin (Refludan )** Argatroban Bivalirudin (Angiomax ) Dabigatran (Pradaxa ) Factor Xa inhibitors Fondaparinux (Arixtra ) Rivaroxaban (Xarelto ) Apixaban (Eliquis )
Anticoagulants Does newer = better?
Anticoagulation Cascade Fondaparinux Rivaroxaban Apixaban Ryan L. Anticoagulation. In Attridge, Miller, Moote, Ryan 2012. Internal Medicine: A Guide to Clinical Therapeutics 1st ed. McGraw-Hill
DVT/PE treatment Warfarin Stop thrombus extension Prophylaxis against repeat TEE Inhibits vitamin K-dependent clotting factors Food/drug interactions Vitamin K-rich foods Enzyme inducers/inhibitors
Delayed onset Warfarin Must deplete pre-formed clotting factors Factor VII t½ 4-6 hours Factor IX t½ 24-36 hours Factor X t½ 36-48 hours Factor II t½ 60 hours Protein C t½ 8 hours Protein S t½ 30 hours Overlap heparin/lmwh with warfarin to treat active clotting process
Warfarin Genomics Unpredictable dose-response Highly protein bound Metabolism R enantiomer CYP1A2, CYP2C19, CYP3A4 S enantiomer CYP2C9 genetic variance VKORC1 (vitamin K epoxide reductase) Mutations in warfarin sensitive alleles Wild type AG (alanine-glutamine sequence ) Warfarin sensitive mutation AA Warfarin resistant mutation GG
Warfarin Pros Monitoring Oral agent Reversible Cost Cheap drug Monitoring costs? Cons Food/drug/disease interactions Delay in onset/offset Monitoring Genetic variability
Heparins DVT/PE treatment Stop thrombus extension TEE prophylaxis doses for prophylaxis Inhibit IIa, Xa Bind to antithrombin (AT), anticoagulant effect UFH AT AT AT Xa AT Factor IIa LMWH AT AT AT Xa AT Factor IIa
Heparins Pros Monitoring Antidote Short t ½ Fast onset Cost Experience in pregnancy, renal insufficiency, obesity Cons Monitoring (UFH) Short t ½ Injectable Heparin induced thrombocytopenia UFH >> LMWH
Fondaparinux (Arixtra ) DVT prophylaxis (>50kg) Hip fracture & replacement surgery Knee replacement surgery Abdominal surgery DVT & PE treatment With warfarin
Off-label uses Fondaparinux DVT prophylaxis in medically ill DVT prophylaxis HIT history HIT treatment Non-ST-segment-elevation MI (non-stemi)
Factor Xa inhibitor Fondaparinux Single-chain pentasaccharide Structure similar to heparin AT binding site Fondaparinux-antithrombin complex Inhibits factor Xa No IIa activity AT AT AT Xa AT Factor IIa
Fondaparinux vs. UFH & LMWH UFH AT AT AT Xa AT Factor IIa LMWH AT AT AT Xa AT Factor IIa Fondaparinux AT AT AT Xa AT Factor IIa
Fondaparinux Contraindications Renal insufficiency Clcr <30mL/min DVT & PE tx <50kg 5mg QD 50 100kg 7.5mg QD >100kg 10mg QD Overlap warfarin 5 days & therapeutic INR Prophylaxis > 50kg 2.5mg QD 6 after surgery Thrombocytopenia No HIT crossreaction*** Long half-life 24 hour dosing Reversibility No antidote
Fondaparinux Rapidly absorbed SQ 100% bioavailable Not metabolized Renal excretion Dose independent elimination t 1/2 = 15 hours Predictable doseresponse relationship AUC linearly correlated to dose No routine monitoring PT & aptt insensitive Heparin/LMWH antixa assay inaccurate AntiXa assay calibrated to fondaparinux Availability Interpretation
Fondaparinux Pros Once daily dosing No monitoring Not contraindicated in HIT Cons No monitoring Injectable Contraindicated Clcr <30mL/min No antidote Short t ½ Cost? HIT?
Rivaroxaban (Xarelto ) Oral Xa inhibitor Take with food Non-valvular afib AHA high risk Prior TIA, stroke or 2 risk factors 20mg daily Cr cl 15 50mL/min 15mg QD Cr cl <15mL/min Contraindicated DVT/PE treatment 15mg BID X3 weeks; then 20mg QD Cr cl <30mL/min Contraindicated DVT prophylaxis Hip/knee replacement 10mg QD Cr cl 30 49mL/min» Use caution Cr cl <30mL/min» Contraindicated
Rivaroxaban Some CYP3A4 metabolism Drug interactions effects 3A4 inhibitors effects with strong 3A4 inducers, P- glycoprotein inducers Contraindications Spinal puncture, caution if recent surgery, plt <50K, trauma, hypertensive crisis Cl cr <15mL/min
Adverse effects Rivaroxaban Bleeding, bruising, thrombocytopenia, LFT Renal clearance t ½ ~ 5-9 hours; 11-13 elderly No differences with weight extremes PT shows linear dose/response Assay dependent Specific curves must be developed locally
No specific antidote Not dialyzable protein binding Rivaroxaban Life-threatening bleed PRBC & aggressive bleeding management 4-factor PCC Reversed measurable effects in healthy subjects Not available in U.S. FDA currently reviewing Behring product
Rivaroxaban Conversions From UFH Dose when DC infusion From LMWH Dose within 2 of next scheduled dose From warfarin Dose when INR <3 To warfarin INR unreliable Initiate warfarin AND parenteral agent 24 after DC To UFH/LWMH Initiate 24 after last rivaroxaban dose
Rivaroxaban Pros Oral agent Once daily dosing After 3 week induction with TEE No monitoring No adjustments with obesity/low body weight Cons No monitoring Renal elimination No antidote Cost Drug interactions Short t ½ Non-compliance Interferes with INR
Apixaban (Eliquis ) Oral Xa inhibitor ARISTOTLE trial CHADS2~2, n=18201 stroke, major bleeding with apixaban AHA 1 additional stroke risk Nonvalvular atrial fibrillation 5mg BID 2.5mg BID if 2 Age 80 Body weight 60kg Scr 1.5mg/dL N Engl J Med 2011;365:981-92
Apixaban DVT/PE (unlabeled use) 2.5mg BID 5mg BID bleeding DVT prophylaxis ADOPT trial Apixaban 2.5mg BID X30 days vs. enoxaparin 40mg QD X6 14 days Not superior to enoxaparin Significantly more bleeding N Engl J Med 2011;365:2167-77
Apixaban Hepatically metabolized CYP3A4>>1A2, 2C8/9/19 Drug transport ABCG2 AKA breast cancer resistance protein P-glycoprotein Renal excretion ~30% unchanged drug Contraindicated Cl cr <25mL/min per AHA; <15mL/min per label Severe hepatic disease Intestinal lumen (apical membrane) Blood (basolateral membrane)
Apixaban Hepatically metabolized CYP3A4>>1A2, 2C8/9/19 Drug transport ABCG2 AKA breast cancer resistance protein P-glycoprotein Renal excretion ~30% unchanged Drug Contraindicated Cl cr <25mL/min per AHA; <15mL/min per label Not recommended in severe hepatic disease Intestinal lumen (apical membrane) Blood (basolateral membrane)
From warfarin Apixaban Conversion Initiate when INR < 2.0 To warfarin Apixaban affects INR Discontinue apixaban, initiate parenteral agent & warfarin when next dose is due
Apixaban Pros Oral agent No monitoring Cons No monitoring Renal elimination No antidote Cost Short t ½ Non-compliance BID dosing
Dabigatran (Pradaxa ) Oral reversible thrombin inhibitor Non-valvular atrial fibrillation 150mg BID RELY trial compared to warfarin in afib Decreased stroke risk & similar overall bleeding No superiority if good warfarin control 2X GI bleed risk intracranial bleed N Engl J Med 2009;361:1139-51
Dabigatran Contraindicated in mechanical heart valves RE-ALIGN trial; terminated early 2/2 increased risk of stroke, MI, mechanical valve thombosis vs. warfarin major bleeding (pericardial effusion) after valve surgery Not evaluated in bioprosthetics Am Heart J 2012;163:931-7
Hygroscopic tablets Dabigatran Dispense/store in original packaging Discard 4 months after opening t ½ ~ 8 single dose, 14 multiple dose Renal clearance Cl Cr 15 30mL/min 75mg BID Contraindicated <15mL/min
Adverse effects Bleeding GI distress No antidote Dabigatran May be reversed by PCC Provides factor II Removed by hemodialysis
Elderly Dabigatran bleeding risk; no specific dosing guidelines Disease-related concerns variability with hepatic impairment Use in advanced liver disease not recommended Renal dysfunction Concentration up to 3X with moderate function American College of Chest Physicians considers Cl cr <30mL/min contraindicated
Drug interactions Dabigatran P-glycoprotein inducers dabigatran concentrations Avoid with strong inducers Rifampin» Undetectable levels 7 days after DC P-glycoprotein inhibitors No dose adjustment required if Cl Cr 30mL/min Verapamil, amiodarone, quinidine, clarithromycin
Dabigatran Conversions From parenteral Dose 2 before next scheduled dose To parenteral 12 after last dabigatran dose 24 if Cl cr < 30mL/min To warfarin Cl cr >50mL/min Initiate warfarin 3 days before DC dabigatran Cl cr 31--50mL/min Initiate warfarin 2 days before DC dabigatran Cl cr 15--30mL/min Initiate warfarin 1 day before DC dabigatran Cl cr < 15mL/min No guidance
Dabigatran Pros Oral agent No monitoring Cons No monitoring Renal elimination No antidote Cost Short t ½ Non-compliance BID dosing
Warfarin Anticoagulant Summary Dosing Monitor? Dose adjust? PO, daily INR UFH SQ, IV anti-xa, aptt LMWH SQ Available Anti-Xa, renal Drug intx? & food Antidote? Cost Yes Yes Yes +/- Fondaparinux SQ No Renal No Rivaroxaban Apixaban Dabigatran PO, daily* PO, BID PO, BID No Renal No No Renal No No Renal No
Meta-Analysis Efficacy Novel oral anticoagulants (NOACs) vs. warfarin Phase III trials in non-valvular afib 3 trials 50578 patients NOACs stroke/embolism; 2.8% vs. 3.5%, OR 0.82; CI 0.74 0.91, P < 0.001» Fewer hemorrhagic strokes Death 6.0% vs 6.3%, OR 0.88, 95% CI 0.82 0.95, P = 0.001 NOACs» intracranial bleed; 0.6% vs. 1.3%, P < 0.001» gastrointestinal bleed; 2.3% vs. 1.3%, P = 0.036 NOACs stroke/systemic embolism, hemorrhagic stroke & mortality Similar risk of major bleeding http://dx.doi.org/10.1016/j.ijcard.2012.03.148
Meta-Analysis Bleeding NOACs & GI Bleeding 43 randomized controlled trials (151,578) vs. standard of care NOAC GIB OR 1.45; CI 1.07-1.97 Atrial fibrillation OR1.21; CI, 0.91-1.61 Orthopedic surgery PPX OR 0.78; CI, 0.31-1.96 VTE OR 1.59; CI, 1.03-2.44 ACS OR 5.21 CI, 2.58-10.53 Apixaban OR 1.23; CI 0.56-2.73 Dabigatran OR 1.58; CI, 1.29-1.93 Rivaroxaban OR 1.48; CI 1.21-1.82 http://dx.doi.org/10.1053/gastro.2013.02.141
Are NOACs Right for YOUR Patients?
NOAC vs. warfarin Questions to ask yourself Does your patient match the patients that were studied? What is your patient s risk for a TEE? Is your patient at increased risk of adverse events? GIB Falls Is your patient compliant? Is cost a factor?