How to Manage Warfarin Management

How to Manage Warfarin Management Katie McClendon, PharmD, BCPS University of Mississippi School of Pharmacy AS MANDATED BY ACCME SPEAKERS ARE ASKED TO DISCLOSE ANY REAL OR APPARENT CONFLICT RELATED TO THE CONTENT OF THEIR PRESENTATION TODAY S SPEAKER HAS NO DISCLOSURE TO MAKE Objectives 1. Describe the CHEST Antithrombotic Guidelines for warfarin management 2. Recognize common and serious drug drug interactions with warfarin and develop plans for managing the interaction 3. Manage non therapeutic anticoagulation *If time, will discuss new anticoagulant options 1

Warfarin Indications Prevention and treatment of venous thromboembolism (VTE), atrial fibrillation (AF), mechanical valve replacement Contraindications Hypersensitivity Hemorrhagic tendencies Severe uncontrolled or malignant hypertension Pericarditis or pericardial effusion Patients with a high potential of noncompliance Eclampsia/pre eclampsia Pregnancy (except women with mechanical heart valves) Vitamin K Antagonist Warfarin (Coumadin, Jantoven) Racemic mixture of R and S enantiomers. S enantiomer is 3 5 x more potent MOA: inhibits the C1 subunit of the VKORC1 enzyme complex, thus reducing regeneration of vitamin K depletion of clotting factors II, VII, IX, X and proteins C and S SN0T (Seven, nine, 10, and two) 2

Chest Guidelines 2008 version was 968 pages, 600 recommendations Can you remember all that? 2012 Update now has 70 page executive summary, total 801 pages http://www.chestnet.org/accp/guidelines/accpantithrombotic guidelines 9th ed now available Included a systematic review of patient values and preferences Used more tables to make content easier to follow and understand Guyatt GH, et al. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9 th Ed: American College of Chest Physicians evidence based clinical practice guidelines (9 th ed). Chest 2012; 141 (2): 7S 47S. TOP 10 VKA RECOMMENDATIONS IN CHEST GUIDELINES Starting Warfarin Start warfarin at 10 mg daily x 2 days in generally healthy patients to be treated outpatient Then check INR Recommend against pharmacogenetic testing to guide initial dose For VTE, start LMWH and warfarin same time 3

Continued Warfarin Don t bother bridging for single subtherapeutic INR in a patient who is normally therapeutic If INR <0.5 out of range in a stable patient, recheck in 1 2 weeks If stable, check INR q12 weeks (not q4 weeks) INR Goals Most need INR 2 3 (goal 2.5) Including: Antiphospholipid syndrome with hx of VTE, AF, aortic valve replacement Mechanical mitral valve replacement INR 2.5 3.5 (goal 3) Chest Guidelines: DDI to Avoid Increased risk of bleeding, so avoid the following if possible: NSAIDs, COX 2 inhibitors, some antibiotics Exception: mechanical valve, ACS, recent coronary stents/bypass surgery WORST Cotrimoxazole Quinolones PROBABLE Cephalosporins Metronidazole Amoxicillin Doxycycline Fluconazole 4

Nursing Home Patient New patient to the nursing home, on long list of medications, including therapeutic warfarin (INR 2.51) and metronidazole Metronidazole therapy completed about 1 week after coming to nursing home What do you expect to happen to the INR? Increase Decrease No change Stopping Warfarin Just stop it VTE after surgery: 3 months VTE with transient RF: 3 months Unprovoked VTE: at least 3 months 2 or more VTE: extended treatment DVT+CA: extended treatment AF cardioversion: start >3 weeks prior, continue >4 weeks after Mechanical valves: continued therapy Don t Stop Til You Get Enough MJ diagnosed with LLE DVT while taking Yaz 3/1/13 You switch to IUD. When can you stop warfarin? 6/1/13 9/1/13 3/1/14 Never 5

Warfarin Therapy 9th ed. Update PRACTICE 8 TH EDITION 9 TH EDITION Loading dose Bridging for patients with acute VTE None; start at 5 10 mg for 1 2 days then adjust based on INR (1B) Start warfarin on day 1 of LMWH or UFH (1A) 10 mg for 2 days in patients sufficiently healthy to be treated outpatient (2C) Start warfarin on day 1 or 2 of LMWH or UFH (2C) Monitoring No less frequent than every 4 weeks for those on stable doses (2C) Single out of range Not previously stated INR Bridging for low INR Monitor at intervals up to 12 weeks for those on stable doses (2B) If INR <0.5 above or below target INR, continue current dose and retest in 1 2 weeks (2C) Not recommended (2C) Vitamin K supplementation Discontinuation Not previously stated Abrupt (2C) Regular supplementation not recommended (2C) Warfarin Kinetics R warfarin s ½ life=45 h S warfarin s ½ life=29h S: CYP2C9, 3A4 2C9 has multiple polymorphisms R: 3A4, 1A2, 2C19 Starting Doses Warfarin Patient Characteristics Healthy and to be treated as outpatients 10 mg Dose Elderly, impaired nutrition, liver disease, CHF, or high risk of bleeding Heart valve replacement 5mg 2 3 mg Check INR in 2 3 days and adjust accordingly to target INR INR of 2 3 for most indications INR of 2.5 3.5 for some high risk indications Mechanical heart valve 6

Warfarin: Factors Affecting INR Increased Effect ( Increased INR) Hyperthyroidism Liver disease Fever Diarrhea/Vomiting HF exacerbation Decreased intake of Vitamin K Acute alcohol use Decreased tobacco/smoking Decreased Effect (Decreased INR) Hypothyroidism Fat malabsorption Increased intake of Vitamin K Chronic alcohol use Increased smoking Increased exercise Warfarin Drug Drug Interactions Increased effect/inr Amiodarone* Propafenone* Metronidazole* Tamoxifen* Bactrim (SMX/TMP)* Cimetidine Corticosteroids Azoles Alcohol Levothyroxine Macrolides (rarely Azithromycin) Phenytoin Omeprazole Decreased Effect/INR Phenobarbital Phenytoin Primidone Rifampin* Carbamazepine Methimazole PTU *major interaction Case example My grandmother: 92 yo with Afib, HF, OP with multiple fractures/falls Fosamax, amiodarone, warfarin, HCTZ Warfarin monitored at cardiologist office Diagnosed with UTI at PCP, given Bactrim DS Pharmacists filled Bactrim without contacting either provider 7

Common, Mild Interactions APAP (higher dose) Still safest option for OTC pain relief Alcohol, including rubbing alcohol Foods Cranberry, grapefruit, other tropical fruits (?) Vit K intake changes Warfarin Side Effects Bleeding! gums, nose, mouth, stools, urine Skin necrosis (rare) Purple toe syndrome Monitoring INR Check After warfarin initiation 2 3 days Until INR in therapeutic range on 2 consecutive INR checks Then every week Until INR in therapeutic range on 2 consecutive INR checks Then every 2 weeks Until INR in therapeutic range on 2 consecutive INR checks Then every 4 weeks When dose is stable, check monthly INR Check for maintenance of warfarin After 1 week If start/stop an interacting medication, diet change, etc. Every 1 2 weeks If dose needed adjustment by 5 10% Every 4 weeks Every 6 12 weeks* If patient maintained on stable dose <6 months If patient maintained on stable dose > 6 months INR Goal 2 3 UMC Warfarin Nomogram Dosage Adjustment INR Goal 2.5 3.5 INR < 2.0 Increase weekly dose by 5 20% INR < 2.5 INR 2.0 3.0 No change INR 2.5 3.5 INR 3.1 3.5 Decrease weekly dose by 0 15% INR 3.1 3.5 INR 3.6 4.0 Hold 0 1 doses, then decrease weekly dose by 10 15% INR 3.6 4.0 INR 4.1 5.9 Hold 1 2 doses, then decrease weekly dose by 10 20% INR 4.1 5.9 INR 6.0 9.0 Hold 2 3 doses, monitor INR more frequently, and restart at a dose 10 20% lower. The patient will be counseled to watch for signs and symptoms of bleeding and to go to the emergency department if bleeding occurs.* INR 6.0 9.0 INR 9.0 INR > 11 Patient to hold medication until directed and will be seen at next clinic day. The patient will be counseled to watch for signs and symptoms of bleeding and to go to the emergency department if bleeding occurs.* If phytonadione (Vitamin K 1) is deemed necessary, oral Vitamin K 1 2.5mg may be prescribed. Patient may be sent to the emergency room.* PT/INR will be repeated and CBC drawn. Physician will be contacted. Patient may be sent to the emergency room. INR 9.0 INR > 11 8

Vitamin K 9 th ed. Update 8 TH EDITION 9 TH EDITION INR <5 with no bleeding: lower warfarin dose (1C) INR >5 but <9 with no bleeding: hold 1 or 2 doses and lower the warfarin dose (1C) INR > 4.5 but < 10 with no bleeding: vitamin K NOT recommended (2B) INR > 10: give low dose vitamin K orally (2C) INR >5 but <9 with risk of bleeding: hold dose and give vitamin K 1 or 2.5 mg PO (2A) INR >5 but <9 requiring surgery: vitamin K PO (will drop INR in 24 hours) (2C) INR > 9 with no bleeding: hold doses and give vitamin K 2.5 mg or 5 mg PO (1B) Serious bleeding regardless of INR: hold warfarin and give vitamin K 10 mg IV slow + FFP, PCC, or recombinant factor VIIa (1C) For major bleeding, give PCC instead of plasma (2C) Additional use of vitamin K 5 10 mg by slow IV injection recommended in addition to reversal with coagulation factors (2C) Warfarin and Pregnancy? Pregnancy Category X, so generally avoid, especially 1 st trimester VTE: LMWH If dx in pregnancy, continue tx at least 6 weeks post partum If trying to conceive, wait until pregnant to switch to LMWH Mechanical valve: LMWH or UFH (monitor anti Xa or appt) Can switch to warfarin after 13 weeks until close to delivery TOP 10 THINGS NOT TO DO WITH A WARFARIN PATIENT 9

Top 10 things to not do with a warfarin patient Follow up in 4 weeks after initial visit Taper warfarin off Continue current warfarin dose if after 1 day the INR is therapeutic Assume that because a patient has a therapeutic INR, there are no problems Prescribe ABX without scheduling close follow up Top 10 things to not do with a warfarin patient Leave a patient on warfarin without periodically re evaluating risk/benefit Forget to ensure use of contraception in women of child bearing potential Over react to sub/supra therapeutic INRs Use Vit K if INR <10 and no bleed Tell patients they can t eat Vit K foods QUESTIONS? 10

WHAT ABOUT THOSE NEW MEDS? Direct Thrombin Inhibitor Dabigatran (Pradaxa) MOA: Specific, reversible, direct thrombin inhibitor that inhibits both free and fibrin bound thrombin. Inhibits thrombin mediated effects Fibrinogen fibrin Activation of factors V, VIII, XI, and XIII Thrombin mediated platelet aggregations 11

Dabigatran (Pradaxa) US Indication: Prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation Canadian indication: Prevention of VTE in patients undergoing total hip or knee replacement surgery Contraindications: Hypersensitivity Active pathological bleed Dabigatran vs. Warfarin Chest guidelines recommend dabigatran over warfarin if: AF+TIA/CVA Dabigatran (Pradaxa) Dosing and Conversions Patient Characteristics Dose CrCl > 30 ml/min 150 mg BID CrCl 30 50 ml/min and concomitant Consider 75 mg BID dronedarone or ketoconazole CrCl 15 30 ml/min 75 mg BID Conversion from parenteral Initiate dabigatran 2 hours prior to the time anticoagulant of the next scheduled parenteral anticoagulant (enoxaparin) or at the time of D/C of continuous parenteral anticoagulant (heparin) Conversion from warfarin D/C warfarin and initiate when INR < 2.0 Conversion to warfarin: Initiation of warfarin based on CrCl CrCl >50 ml/min: initiate 3 days before D/C of dabigatran CrCl 31 50 ml/min: 2 days before D/C of dabigatran CrCl 15 30 ml/min: 1 day before D/C of dabigatran 12

Common Side Effects Gastritis like symptoms Bleeding (mostly GI) Monitoring Efficacy None Required Safety Renal function at baseline and yearly in patients >75 yo and those with CrCl < 50 ml/min Antidote None Dabigatran (Pradaxa) Of note: Pregnancy Category C Storage Concerns Once bottles are opened, must use within 4 months! Keep in original package; protect from moisture. Factor Xa Inhibitor Rivaroxaban (Xarelto) MOA: Inhibits platelet activation and fibrin clot formation by direct, selective, and reversible inhibition of Factor Xa. Factor Xa catalyzes the conversion of prothrombin to thrombin which then activates the conversion of fibrinogen fibrin = clot! 13

Rivaroxaban (Xarelto) Indications Stroke prevention in patients with nonvalvular Atrial fibrillation Post Operative DVT/PE prophylaxis Knee replacement surgery Hip replacement surgery Contraindications Hypersensitivity Active major bleeding Moderate to severe hepatic impairment associate with coagulopathy (Canadian labeling) Rivaroxaban (Xarelto) Dosing Patient Characteristic CrCl > 50 ml/min Non valvular Atrial Fibrillation Dosing 20 mg po daily with evening meal CrCl 15 50 ml/min 15 mg po daily with evening meal Post Operative Thromboprophylaxis Knee Replacement 10 mg once daily x 12 14 days. Initiate 6 10 hours postoperatively Hip Replacement 10 mg once daily x 35 days. Initiate 6 10 hours postoperatively Rivaroxaban (Xarelto) Conversion Conversion from warfarin Action Discontinue warfarin and initiate rivaroxaban as soon as INR <3.0 Conversion to warfarin Conversion from continuous IV heparin Initiate warfarin and a parenteral anticoagulant 24 hours after D/C rivaroxaban Initiate rivaroxaban at the time of heparin discontinuation Conversion to continuous heparin Initiate heparin 24 hours after D/C of rivaroxaban 14

Rivaroxaban (Xarelto) Common Side Effects Bleeding Headache Monitoring None Antidote None Black Box Warnings: Patients receiving spinal epidural or spinal puncture are at risk of hematoma and paralysis D/C of therapy in patients with AF can put patients at increased risk of thrombotic events Other 9 th ed. Updates TOPIC 8 TH EDITION 9 TH EDITION Dabigatran Not included Recommended OVER warfarin for patients with atrial fibrillation needing oral anticoagulation (2B) Rivaroxaban Not included Recommended as a prophylactic option for total hip/knee arthroplasty patients, orthopedic patients who are uncooperative with injections or an IPCD LMWH recommended over dabigatran or rivaroxaban for long term therapy in patients with DVT or PE who are not receiving VKA therapy (2B/2C). Apixaban (Eliquis) Direct factor Xa inhibitor Approved for stroke prevention in AF Dose: 5 mg BID 2.5 mg BID if 2 or more of the following: >80 yoa, weight <60 kg, SCr>1.5 mg/dl 15

Apixaban (Eliquis) DDI: avoid with inducers of CYP3A4 and P glycoprotein Carbamazepine, phenytoin, phenobarbital, St. John s wort, rifampin Monitoring: None Antidote: NONE Number needed to treat and harm For Atrial Fibrillation (vs. warfarin): Eliquis (apixaban) 3 fewer strokes per 1000 patients per year, 10 FEWER bleeds, and 4 FEWER deaths Pradaxa (dabigatran) 5 fewer strokes per 1000 patients per year; similar overall bleeding risk Xarelto (rivaroxaban) similar strokes and risk of major bleeding BUT only one given once/day Warfarin: only one with an antidote, only one for mechanical valves, and treatment costs less ($80 vs $250). Pharmacists Letter 16

QUESTIONS? 17