Anticoagulant Management Janel Liane Cala PGY1 Pharmacy Resident Medical Center Hospital
Objectives Review warfarin management Literature review for new oral anticoagulants (NOACs) in atrial fibrillation Clinical pearls for the management of NOACs
Bleeding Risk VS Stroke Risk Total % Bleeding Total % Stroke HAS- CHADS2 BLED Score Score 1 2.8% 1 3.4% 2 4.0% 2 4.1% 3 5.9% 3 5.8% 4 8.5% 4 8.9% 5 and 6 > 8.5% 5 9.1% 6-8 Unable to predict due to Stroke history = automatic small patient high risk population
Warfarin Management
Protein C and S Warfarin (natural anticoagulant proteins)
Factor Half-life (hour) VII 4-6 IX 21-30 X 27-48 II 42-72 Protein C* 8 Protein S* 60 • Initial INR elevation = factor VII depletion • Initial procoagulant state during warfarin therapy • Full Antithrombotic effect= 5-7 days
Pharmacokinetics Absorption : 100% bioavailability Distribution : 98% protein bound --- Unbound drug: active Metabolism : CYP 2C9 CYP2C9 inhibitors: Amiodarone, Statin* (Simvastatin, Rosuvastatin), Fibrates AbX (Bactrim, Flagyl), Azoles Elimination : t ½ 20 – 60 hrs
Factors Influence Warfarin Dose Requirement Goal INR Interacting medications Dietary vitamin K (must be relatively consistent) Alcohol use Underlying disease states (eg hepatic disease, hypoalbuminemia) Age Genetic factors
Drug- Drug Interactions
Dose Initiation Strategy Starting dose = an educated guest Inpatient allows daily INR monitoring and dose adjustment utilize flexible dose initiation 10 mg vs 5 mg initiation Faster therapeutic INR attainment Supratherapeutic INR, bleeding, and initial risk of clotting Adjustment based on rate of INR change after the first 1 to 3 doses
Monitoring Prothrombin time (PT) Measured by adding calcium and a tissue thromboplastin to plasma INR = international normalized ratio
INR Goals CONDITION TARGET INR DVT/ PE 2 - 3 Afib 2 - 3 Mechanical Heart valves 2.5 – 3.5
Frequency of INR Monitoring INITIATION Inpatient Daily until stable, then every 3-5 days After hospital discharge (at least weekly) - STABLE - Within 5-7 days - UNSTABLE - Within 1-3 days Stable* - at least 2 consecutive therapeutic INRs
Frequency of INR Monitoring LONG TERM MAINTENANCE INR > 3.5 ; dose held today 7 days the latest Dosage change today Within 1-2 weeks Routine follow up q 4-6 weeks stable, compliant Routine follow up q 1 -2 weeks Unstable, non-compliant Consider other OAC Stable* - at least 2 consecutive therapeutic INRs
Dosage size 1mg (Pink) 5mg (Peach) 2mg (Lavender) 6mg (Teal) 2.5mg (Green) 7.5mg (Yellow) 3mg (Tan) 10mg (White) 4mg (Blue)
Warfarin Reversal Fresh Frozen Plasma Contains all coagulation factors Act rapidly but short acting, should be used for emergent reversal of elevated INRs Initial dose of FFP based on risk of bleeding Low to moderate risk – FFP 2 units High risk or active bleeding – FFP 4 units INR should be rechecked 1 hour after administration of FFP.
Warfarin Reversal Vitamin K (Phytonadione) PO - safest and most reliable route reduce INR back to the therapeutic range within 24hr without causing complete reversal or prolonged warfarin resistance IV - reserve for active bleeding quickly reverse INR can lead to extended warfarin resistance Vitamin K 10 mg / 100mL NS, infuse over 60 minutes (anaphylactic rxn) SQ and IM should be avoided
Kcentra (4F- PCC) Components: Factors II, VII, IX, X, Proteins C and S, Antithrombin III, small amount of heparin and human albumin Contraindication: disseminated intravascular coagulation, heparin-induced thrombocytopenia Dosed on amount of factor IX: 500 units/vial
FFP KCentra Type specific Not blood group specific; ( must be ABO compatible) No need to thaw Dosed by Volume Dosed by Factor IX units 8 vials Kcentra = 16 units (4L) FFP 8 vials Kcentra = 16 units (4L) FFP Cheaper Correct INR faster Similar effect on INR after 24 Faster rate of administration hours $500u/vial
Special Population and Warfarin Elderly (>75) Pregnancy and lactation: stippled calcification and nasal cartilage hypoplasia Alcoholism: alcohol inhibit warfarin metabolism. Binge drinking increases bleeding risk from elevated INR and risk of falls. Renal disease and hemodialysis: lower dose may be required due to decrease CYP2C9 activity Hypo-thyroidism decreases catabolism of clotting factors increase warfarin dose requirement Adjust warfarin dose when start or stop thyroid medication
New Oral Anticoagulants Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Epixaban (Eliquis) Edoxaban (Savaysa)
Rivaroxaban Apixaban Edoxaban Dabigatran
NOACs Literature For Stroke Prevention in Patients with Atrial Fibrillation (SEE HANDOUT) Rivaroxaban- high risk patients (high CHADS2) • Apixaban- lower bleeding risk (equivalent to aspirin, better • than warfarin in both GIB and ICB)
Case 1 MH is a 50 y/o male with PMH of chronic afib, heart failure, hypertension (SBP around 140 at home), stroke, and diabetes type 2. He is compliant with his warfarin regimen but want to switch to another agent because it is difficult for him to attend warfarin clinic on a regular basis. What is/are your approach to this situation?
Case 1 CHADS2 = 5 (> 8.5%) HAS-BLED = 1 (3.4%) ↑ CHADS2 ↓HASBLED Rivaroxaban – once daily, study population has high average CHADS2 If home INR is available, can also arrange home INR and follow up via phone
Case 2 Similar patient as above, but age = 80, alcoholic, taking ASA daily and hypertension is uncontrolled. ↑CHADS2 CHADS2 = 6 (> 8.5%) ↑HASBLED HAS-BLED = 5 (9.1%) Apixaban due to lower bleeding risk (equivalent to aspirin, better than warfarin in both GIB and ICB)
Case 3 70 y/o with chronic afib, uncontrolled HTN, alcoholic, taking ASA daily for history of MI. CHADS2 = 1 (2.8%) HAS-BLED = 4 (8.9%) ↓CHADS2 ↑HASBLED Anticoagulant risk may outweigh benefit in this patient
NOAC >>> Warfarin Patient can afford NOACs or qualify for patient assistance Difficult to monitor/control INR Patient cannot come to clinic and home monitoring is not available INR is unstable
Warfarin >>> NOAC 1. Relative medication non-compliance (forget a dose occasionally) due to short T1/2 of all NOACs 2. Patient’s reference – would like to see INR to know that it is working 3. Indications that NOACs has not been studied (HIT, cancer patients, etc.)
NOAC Dosing No loading dose for atrial fibrillation No bridging required (peak between 2-4 hours) Renal dose adjustment (see hand out) Apixaban 50% dose if patient meets at least 2/3 criteria: age > 80 y/o, weight < 60kg, or Scr > 1.5
Conversion to and from NOACs Heparin drip to NOACs: start NOACs at time of heparin drip discontinuation, may wait 2-4 hours to initiate NOACs if concern about bleeding risk Lovenox to NOACs: give NOACs at the next scheduled Lovenox dose Warfarin to NOACs: Wait until INR < 2 to initiate NOACs
Drug to Drug Interaction
Dosing Error Missed dose: Do not double dose Use half-way rule Accidental Double dose: Skip a dose for BID NOAC For Daily dose: Continue the normal dosing regimen without skipping the next daily dose
Bleeding While Using a NOAC
Elective Surgery Minimal bleeding risk procedures: dental intervention, cataract or • glaucoma, endoscopy without surgery, superficial surgery Low bleeding risk interventions: endoscopy with biopsy, prostate or • bladder biopsy, electrophysiological ablation, angiography, pacemaker or ICD implantation High risk surgeries: complex left sided ablation, spinal or epidural • anesthesia, lumbar puncture, thoracic surgery, abdominal surgery, major orthopedic surgery, liver biopsy, kidney biopsy
References Wittkowsky AK. Chapter 24: Warfarin (AHFS 20:12.04). Available at 1) http://www.ashp.org/doclibrary/bookstore/p2548/sample- chapter-24.pdf. Accessed July 2015. Connolly SJ, Ezekowitz MD, Yusul S, et al. Dabigatran versus 2) warfarin in patients wth atrial fibrillation. NEJM . 2009;361:1139-51. Granger CB, Alexander JH, Mcmurray JJ, et al. Apixaban versus 3) warfarin in patients with atrial fibrillation. NEJM. 2011;11:981-992. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with 4) atrial fibrillation. NEJM . 2011;364:806-17. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin 5) in non-valvular atrial fibrillation. NEJM. 2011;365:883-91 Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin 6) in patients with atrial fibrillation. NEJM. 2013;369:2093-104. Heidbuchel H, Verhamme P, Alings M, et al. European heart rhythm 7) association practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2013;15:625-651.
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