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Outpatient Anticoagulation Management Evaluating the pharmacist’s role in the past, present, and future Jill Hiers, Pharm.D., BCPS NHPA CE program December 4, 2016 Outline • Definition of anticoagulation and brief review of clotting cascade • Indications for anticoagulation (CHEST guidelines) • Oral anticoagulants review • Mechanism of action, laboratory monitoring, pharmacokinetics, dosing, adverse effects, reversal, drug interactions, and dietary considerations • Outpatient anticoagulation management • Past • Present • Future Objectives At the end of this presentation, you will be able to: 1. Understand the coagulation process and indications for anticoagulation 2. Calculate a CHA2Ds2-VASc score for a patient with atrial fibrillation 3. Know the oral anticoagulants that are currently available for use, including dosing, monitoring, adverse effects, reversal, drug interactions, and dietary considerations 4. Determine an appropriate oral anticoagulant for a patient 5. Discuss the pharmacist’s current and future role in outpatient anticoagulation management About me • Graduate of University of Connecticut School of Pharmacy • PGY-1 residency at Lahey Clinic (focus in ambulatory care) • Elliot Health System clinical pharmacist since 2007 • Started ambulatory care program in 2008 • Elliot Senior Health Center: medication therapy management, disease management, medication adherence program for seniors (MAPS) • Started residency program in 2008 • 3 residents (one with focus in ambulatory care) • Expansion of anticoagulation clinic program • Outpatient management of anticoagulation therapy Elliot Health System Anticoagulation Clinics • 2002 • One pharmacist managing INR lab results via phone at one primary care office • 2007 • One anticoagulation certified nurse performing point of care (POC) finger stick INR testing and managing results using protocol • 50 POC tests/week • Pharmacist oversight and consultation • 2016 • Four anticoagulation certified nurses working at four different sites, performing POC testing and adjusting warfarin doses per protocol • ~850-1000 POC tests/month (in addition to over-the-phone monitoring) • Pharmacist oversight and consultation has continued Why Anticoagulation Clinics? • Physician managed anticoagulation versus anticoagulation clinics • Literature shows improved time in therapeutic range with anticoagulation clinic management over physician management for patients receiving warfarin therapy • Literature also shows improved satisfaction with anticoagulation clinic management over physician management • Literature supports collaboration with pharmacists, nurses, and physicians (Elliot Health System model) Young S, Bishop L, Twells L et al. “Comparison of pharmacist managed anticoagulation with usual medical care in a family medicine clinic”. BMC Fam Pract. 2011. 12:88 doi: 10.1186/1471-2296-12-88 Anticoagulation • What is anticoagulation? • Anti = against coagulation = clotting • Coagulation is a complex process that allows blood to clot • What are anticoagulants? • Medications that prolong the time it takes for blood to clot Clotting cascade http://www.neurology.org/content/78/7/501/F2.large.jpg. Accessed June 21, 2016. Chest guidelines • Published by the American College of Chest Physicians • Provide guidelines for anticoagulation based on comprehensive literature reviews • February 2012: 9th edition published • January 2016: Updated edition released (VTE) • Updated 12 topics from 2012 version Anticoagulation indications • Venous thromboembolism • Deep vein thrombosis (DVT) • Pulmonary embolism (PE) • Atrial fibrillation • Mechanical or bioprosthetic heart valve • Inherited thrombophilias • Genetic predisposition to clotting • Cardioembolic ischemic stroke • Myocardial infarction (MI) Thrombotic disease burden • Over 900,000 cases of VTE annually • Estimate 1/3 will have reoccurrence over the next 10 years • Approximately 5-8% of the population has an inherited thrombophilia • 2.7-6.1 million Americans have atrial fibrillation • 9% of people over the age of 65 Data and Statistics. http://www.cdc.gov/ncbddd/dvt/data.html. Last accessed September 30, 2016 Atrial fibrillation • Irregular heart rhythm characterized by rapid and irregular heart beats • Irregular rhythm causes blood stasis in the left atrium, which increases risk of stroke True or False Everyone with atrial fibrillation needs to be on an anticoagulant to reduce the risk of a thromboembolic event FALSE!!!! CHA2Ds2-VASc Condition Points C Congestive heart failure (or LV systolic dysfunction) 1 H Hypertension 1 A2 Age greater than or equal to 75 2 D Diabetes mellitus 1 S2 Prior stroke or TIA or thromboembolism 2 V Vascular disease 1 A Age 65-74 1 Sc Female 1 http://www.mdcalc.com/cha2ds2-vasc-score-for-atrial-fibrillation-stroke-risk/. Last accessed September 27, 2016. Annual stroke risk CHA2DS2-VASC Score Stroke risk % 0 0 1 1.3 2 2.2 3 3.2 4 4.0 5 6.7 6 9.8 http://www.mdcalc.com/cha2ds2-vasc-score-for-atrial-fibrillation-stroke-risk/. Last accessed September 27, 2016. CHA2Ds2-VASc SCORE RISK ANTICOAGULATION THERAPY 0 Low None (consider adding aspirin 75-325 mg daily) 1 Moderate Oral anticoagulation or aspirin (above dosing) 2 or greater High Oral anticoagulation http://www.mdcalc.com/cha2ds2-vasc-score-for-atrial-fibrillation-stroke-risk/. Last accessed September 27, 2016. Patient case AW is a 74 year old female recently diagnosed with atrial fibrillation. She has a history of hypertension and her blood pressure is well-controlled with lisinopril 10 mg daily. She also takes a calcium and vitamin D supplement daily. She is going to start on metoprolol XL 25 mg daily for rate control. What is her CHA2DS2-VASc? Would you manage her with an anticoagulant? Patient case AW is a 74 year old female recently diagnosed with atrial fibrillation. She has a history of hypertension and her BP is well-controlled with lisinopril 10 mg daily. She also takes a calcium and vitamin D supplement daily. CHA2DS2-VASc score: 1 point for hypertension, 1 point for age, and 1 point for being female = score of 3 Would you manage her with an anticoagulant? Yes! CHA2Ds2-VASc Calculator • CHA2DS2-VASc Calculator http://www.mdcalc.com/cha2ds2-vasc-score-for-atrial-fibrillation-stroke-risk/. Last accessed September 27, 2016. Anticoagulants • ISMP* high-risk medication • Bear heightened risk of causing significant patient harm when they are use. • The Joint Commission: Hospital national patient safety goal number 3 • Reduce the likelihood of patient harm associated with the use of anticoagulant therapy • Use approved protocols for management of anticoagulant therapy • Obtain baseline laboratory work and provide ongoing lab monitoring (have policy) • Provide ongoing education to prescribers, staff, patients, and families *Institute for Safe Medication Practices http://www.ismp.org/selfassessments/hospital/2011/definitions.pdf. Last accessed September 27, 2016 http://www.jointcommission.org/assets/1/6/2015_NPSG_HAP.pdf. Last accessed September 27, 2016 True or false Anticoagulants dissolve blood clots FALSE!!!! Anticoagulants prevent new blood clots from forming and prevent existing blood clots from getting bigger Patient case It’s the year 2009… ML is a 64-year-old male with history of hypertension who is seen in the emergency department (ED) for increased shortness of breath. He is diagnosed with 6 pulmonary emboli (PE). He is started on enoxaparin (Lovenox®) 1 mg/kg BID in the ED, and needs to be discharged on an oral medication. How would this patient’s PE be managed back in 2009? Oral anticoagulants Prior to 2010: • Warfarin (Jantoven®, Coumadin®) Warfarin • Approved for human use in 1954 • Brand names: Jantoven®, Coumadin® • Available in the following strengths (daily dose varies): • Same color for different strengths regardless of manufacturer: “Please let Greg Brown bring peaches to your wedding” Warfarin Mechanism of action: inhibits vitamin K epoxide reductase vitamin K-dependent clotting factors II, VII, IX, and X, as well as anticoagulant proteins C and S Warfarin pharmacokinetics • Warfarin is an enantiomer (S is 3-5x more potent than R) • Absorption: • Complete oral absorption, peak concentrations in 4 hours • Distribution: • Small volume of distribution, highly protein bound (99%) • Metabolism: • CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4 • Elimination: • Inactive metabolites excreted in urine; • R-warfarin half-life 37-89 hours; S-warfarin half-life 21-43 hours Warfarin Depletion of factors II, VII, IX and X takes time • Factor VII half-life: 4-6 hours • Factor IX half-life: 24 hours • Factor X half-life: 48-72 hours • Factor II half-life: 60 hours • Protein C half-life: 8 hours • Protein S half-life: 30 hours Risk of hypercoaguable state during first few days of treatment due to depletion of protein C and S Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Warfarin • Administration: • Take po (by mouth) once daily with or without food (usually in the evening) • Take at same time every day • Pregnancy/Breastfeeding • Pregnancy category X • Major congenital malformations, fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality • Compatible with breastfeeding https://www.drugs.com/pro/warfarin.html. Last accessed September 27, 2016. Warfarin Lab monitoring • Warfarin prolongs prothrombin time (dependent on factors II, VII and X) • International Normalized Ratio (INR) • Standardized measurement of how long it takes blood to clot • INR = (prothrombintest / prothrombincontrol)ISI • ISI = international sensitivity index • Warfarin dosing depends on INR results http://www.myvmc.com/investigations/blood-clotting-international-normalised-ratio-inr/ Last accessed September 27, 2016. Warfarin indications and INR range Indication INR goal range Venous thromboembolism (VTE): Deep vein thrombosis (DVT) or pulmonary embolism (PE) 2.0-3.0 Atrial fibrillation CHA2DS2-VASc score 1 or greater 2.0-3.0 Cardioversion to normal sinus rhythm 2.0-3.0 Comments Enoxaparin preferred for VTE with malignancy 3 weeks precardioversion and 4 weeks post Holbrook A, Schulman S, Witt D, et al. Evidence Based Management of Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed. American College of Chest Physicians Evidence Based Clinical Practice Guidelines. CHEST. 2012;141:e152s-184s. http://www.uwhealth.org/files/uwhealth/docs/pdf2/Ambulatory_Warfarin_Guideline.pdf Last accessed September 27, 2016 Warfarin indications and INR range Indication INR goal range Comments Valvular heart disease Mechanical heart valves 2.0-3.0 (aortic) 2.5-3.5 (mitral) Bioprosthetic valves aspirin or short-term warfarin then aspirin Ischemic stroke Cardioembolic stroke or TIA 2.0-3.0 Non-cardioembolicuse antiplatelet Can use aspirin 81-325 mg daily Thrombophilias: Antiphospholipid Syndrome Homozygous Factor V Leiden Deficiency of Protein C, S or Anti- Thrombin 2.0-3.0 Holbrook A, Schulman S, Witt D, et al. Evidence Based Management of Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed. American College of Chest Physicians Evidence Based Clinical Practice Guidelines. CHEST. 2012;141:e152s-184s. http://www.uwhealth.org/files/uwhealth/docs/pdf2/Ambulatory_Warfarin_Guideline.pdf Last accessed September 27, 2016 Warfarin duration of therapy Indication Duration of therapy VTE At least 3 months then re-evaluate Extended for second episode of unprovoked Atrial fibrillation Long-term Mechanical heart valves Long-term Ischemic stroke Cardioembolic stroke or TIA 3-6 months; long-term Thrombophilias Indefinite Holbrook A, Schulman S, Witt D, et al. Evidence Based Management of Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed. American College of Chest Physicians Evidence Based Clinical Practice Guidelines. CHEST. 2012;141:e152s-184s. http://www.uwhealth.org/files/uwhealth/docs/pdf2/Ambulatory_Warfarin_Guideline.pdf Last accessed September 27, 2016 Warfarin adverse effects • Common (greater than 10%) • Bleeding • Rare (less than 1%) • Intracranial bleeding • Skin necrosis • Tissue necrosis • Purple toe syndrome • Usually occurs within 3-8 weeks of warfarin initiation • Bleeding into blood vessel plaque cholesterol embolization in feet (and sometimes hands) • Must stop warfarin! Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Purple toe syndrome Bleeding • Signs and symptoms of bleeding: • • • • • • • • • • Nosebleeds Bleeding gums Coughing up blood Abnormal vaginal bleeding Bright red blood when using restroom “Coffee ground” vomit Black, tarry stools (ask about iron!) Bloody or brown urine Unexplained bruising Severe headache Clotting • Signs and symptoms of clotting: • • • • • • • Severe pain/swelling/redness in arms or legs Sudden shortness of breath Chest pain Severe headache/dizziness Slurred speech Sudden changes in vision STROKE! Sudden weakness in arms or legs HAS-BLED • From a one year observational study of over 5000 atrial fibrillation patients on anticoagulation • Estimates risk over 1 year of major bleeding • Major bleeding: bleeding requiring hospitalization, decrease in hemoglobin more than 2 g/L, and/or patient requiring transfusion • Assigns 1 point for different risk factors • Points correlate with risk of bleeding while on anticoagulants http://www.mdcalc.com/has-bled-score-for-major-bleeding-risk/ Last accessed September 27, 2016. HAS-BLED • Hypertension • Abnormal renal and liver function • Stroke • Bleeding • Labile INRs • Elderly • Drugs or alcohol http://www.mdcalc.com/has-bled-score-for-major-bleeding-risk/ Last accessed September 27, 2016. HAS-BLED Condition Points H Hypertension (uncontrolled; systolic over 160 mmHg) 1 A Abnormal renal function (dialysis, transplant, SCr* over 2.26 mg/dl) Abnormal liver function (cirrhosis, bilirubin 2x upper limit of normal, AST/ALT/AP 3X upper limit of normal) 1 1 S Stroke (prior history of stroke) 1 B Bleeding (predisposition to bleeding or prior major bleeding) 1 L Labile INRs (time in therapeutic range less than 60%) 1 E Elderly (age over 65) 1 D Drugs (medication usage that predisposes to bleeding) Alcohol (greater than 8 drinks per week) 1 1 *SCr = serum creatinine http://www.mdcalc.com/has-bled-score-for-major-bleeding-risk/ Last accessed September 27, 2016. HAS-BLED HAS-BLED score Risk 0 0.9% over 1 year; 1 major bleed per 100 patients; low risk 1 3.4% over 1 year; 1 major bleed per 100 patients; low risk 2 4.1% over 1 year; 2 major bleeds per 100 patients; moderate risk 3 5.8% over 1 year; ~4 major bleeds per 100 patients; high risk 4 8.9% over 1 year; ~9 major bleeds per 100 patients; high risk 5 9.1% over 1 year; 12 major bleeds per 100 patients; high risk 6-9 Scores over 5 too rare to determine risk http://www.mdcalc.com/has-bled-score-for-major-bleeding-risk/ HAS-BLED calculator • http://www.mdcalc.com/has-bled-score-for-majorbleeding-risk/ http://www.mdcalc.com/has-bled-score-for-major-bleeding-risk/ Last accessed September 27, 2016. HAS-BLED score • RG is an 81 year old recently diagnosed with atrial fibrillation with a CHA2DS2-VASc score indicating anticoagulation therapy. She has a history of hypertension (BP well controlled with SBP less than 140 mmHg) and spinal stenosis for which she uses acetaminophen 500 mg BID with effect. She was previously taking NSAIDs, but had a major GI bleed and discontinued therapy. Her only other medications include hydrochlorothiazide 25 mg daily for hypertension and calcium/vitamin D. Her recent SCR and CrCl were within normal limits. She occasionally drinks ETOH (1 drink/week). She is concerned about bleeding side effects from anticoagulation therapy. • What is RG’s HAS-BLED score? HAS-BLED score • 1 point for age (over 65) • 1 point for history of previous major bleed • Her hypertension is controlled, so no points • HAS-BLED score = 2 (moderate bleeding risk) • Would start anticoagulation therapy, but educate patient on signs and symptoms of bleeding to watch out for http://www.mdcalc.com/has-bled-score-for-major-bleeding-risk/ Last accessed September 27, 2016. Warfarin reversal • Indications for reversal of warfarin anticoagulation: • Severe bleeding • Surgery • Supratherapeutic INR Warfarin reversal Garcia and Crowther. Reversal of warfarin. Circulation. 2012;125 (23) Warfarin reversal No significant bleeding INR less than 10 No vitamin K INR greater than 10 Consider 2.5-5 mg oral vitamin K Urgent reversal with any INR elevation *Severe/major bleeding * Life threatening hemorrhage *Urgent surgery required Vitamin K 10 mg IV piggy back over 30 minutes AND 3 factor PCC (Profilnine®) AND 1-2 units of fresh frozen plasma Prothrombin complex concentrates • 3-PCC (Profilnine ®, Bebulin®) • Contains factors II, IX and X with minimal factor VII • Usually used in combination with factor VII and FFP and vitamin K • 4-PCC (Kcentra®) • Contains therapeutic concentrations of factors II, VII, IX and X Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Warfarin interruption • Sometimes anticoagulant therapy need to be stopped for a planned procedure • Warfarin interruption depends on the bleeding risk associated with the procedure Procedure bleeding risk High bleeding risk Low bleeding risk Minimal bleeding risk Cancer surgery Major orthopedic Reconstructive Transurethral prostate resection, bladder resection or tumor ablation Nephrectomy, kidney biopsy Colonic polyp resection Bowel resection (PEG) placement, ERCP Procedure duration >45 minutes) Pacemaker implant* Minor dental procedures Cutaneous/lymph node biopsy Shoulder/foot/hand surgery Coronary angiograph Gastrointestinal endoscopy or Colonoscopy +/- biopsy Abdominal hysterectomy Lap. Cholecystectomy Abdominal hernia repair Hemorrhoidal surgery Bronchoscopy +/- biopsy Epidural inj w/ INR <1.2 Pacemaker battery change Arthroscopy Minor derm procedures Cataracts Dental cleanings and fillings *Recent evidence suggests lower risk Management of anticoagulation in the per-procedural periodhttp://qio.ipro.org/wpcontent/uploads/2015/10/AQIN_MAP_5-1-2014.pdf Last accessed September 27, 2016 Warfarin interruption • Do not interrupt warfarin for minimal bleeding procedures • Warfarin interruption for low and high risk bleeding procedures also depends on patient’s thromboembolic risk Management of anticoagulation in the per-procedural period. http://qio.ipro.org/wpcontent/uploads/2015/10/AQIN_MAP_5-1-2014.pdf Last accessed September 27, 2016 Warfarin interruption High risk bleed Low risk bleed High risk clot • Any mechanical mitral valve • Stroke w/in last 6 months (valve) • CHA2DS2-VASc greater than 5 • Stroke w/in last 3 months (AF) • VTE last 3 months • Thrombophilias Interrupt warfarin therapy and bridge with LMWH* Consider interrupting warfarin; bridge if interrupting warfarin therapy Medium risk clot • Aortic valve with high stroke risk • CHA2DS2-VASc 3-4 • VTE last 3-12 months • Recurrent VTE • Cancer Interrupt warfarin therapy and consider bridge with LMWH Consider interrupting with or without LMWH bridge Low risk clot • Aortic valve with low stroke risk • CHA2DS2-VASc less than 2 • VTE more than 12 months ago Interrupt warfarin; bridge not indicated Interrupt warfarin; bridging not necessary *low molecular weight heparin Management of anticoagulation in the per-procedural period. http://qio.ipro.org/wpcontent/uploads/2015/10/AQIN_MAP_5-1-2014.pdf Last accessed September 27, 2016 Warfarin interruption • Hold warfarin 5 days prior to procedure • If indicated, bridge with LMWH • Enoxaparin (Lovenox®) 1 mg /kg BID (1 mg/kg daily if CrCl less than 30 ml/min) • Baseline platelets, H/H, serum creatinine • Start LMWH when INR is less than 2.0 • Last dose of LMWH at least 24 hours prior to procedure • Resume warfarin in the evening after procedure • Resume LMWH on day 1 post procedure (low bleeding risk) or day 2 post procedure (high bleeding risk) Douketis JD, Spyropolous AC, Spencer FA et al. “Perioperative Management of Antithrombotic Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines”. Chest. 2012;141(2_suppl):e326S-e350S. Warfarin drug interactions Risk of increased INR Acetaminophen (vitamin K cycle) Macrolides (2C9 inhibition) Allopurinol (2C9 inhibition) Metronidazole (2C9/3A4 inhibition) Amiodarone (2C9 inhibition) Phenytoin (displaces protein binding sites) Antibiotics (decrease gut flora that produces vitamin K) Proton pump inhibitors (2C9 inhibition) Corticosteroids (unknown) Quetiapine (2C9/3A4 inhibition) Fluconazole (2C9 inhibition) *SSRIs Fluoroquinolones (2C9 inhibition) TCAs (increased warfarin absorption) Levothyroxine (increased metabolism of clotting factors) Trimethoprim/sulfamethoxazole (2C9 inhibition) (some 2C9 inhibition; also decreased platelet aggregation) *SSRIs selective serotonin reuptake inhibitors **TCAs tricyclic antidepressants Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Warfarin drug interactions Risk of decreased INR Anti-thyroid medication (decreased metabolism of clotting factors) Phenytoin (2C9 induction) Barbiturates (2C9 induction) Rifampin (2C9 induction) Bile acid sequestrants (decreased warfarin absorption) St John’s Wart (2C9 induction) Carbamazepine (2C9 induction) Sucralfate (decreased warfarin absorption) Diuretics* (increased concentration of clotting factors) Therapeutic multivitamins (if contain vitamin K Nafcillin (2C9 induction) *Ethacrynic acid displaces warfarin from binding sites and can increase INR Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Warfarin drug interactions Increased risk of bleeding Aspirin Anti-platelet agents Non-steroidal anti-inflammatory drugs (NSAIDs) Fish oil SSRIs SNRIs (selective norepinephrine reuptake inhibitors) Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. True or False Patients taking warfarin should never eat foods rich in vitamin K since vitamin K decreases the effectiveness of warfarin FALSE!!!! Vitamin K rich foods can decrease the INR, but the key is consistency in diet and monitoring Warfarin dietary interactions Foods the decrease INR Foods that increase INR Vitamin K containing foods* Cranberries (sauce, juice, etc.) High protein food/drinks Grapefruit (fruit, juice, etc.) Foods containing bromelain (pineapple, other tropical fruits) Alcohol Dietary consistency is key to keeping INR in therapeutic range! *see vitamin K resource for comprehensive list of vitamin K containing foods: QAS vitamin K registry. http://www.pkdiet.com/pdf/vit/vitkreg.pdf. Last accessed September 27, 2016 Vitamin K containing foods Low vitamin K (0-9 mcg) Medium vitamin K (10-24 mcg) High vitamin K (25 or more mcg) Apples Blackberries/blueberries Asparagus Berries (strawberries/raspberries) Celery Avocado Corn Cucumber (with skin) Broccoli Cucumber (without skin) Grapes (red or green) Brussel sprouts Lettuce (butterhead) Lettuce (iceberg/romaine) Cabbage Oil (olive, peanut) Oil (vegetable) Kale Onions Peppers (green/red-cooked) Mayonnaise Peaches Pistachios Peas Peppers (green/red-raw) Plums (canned) Pumpkin (canned) Tomatoes Tomato paste Spinach Tea (chamomile, decaf) Vegetable juice (canned) Tea leaves (black, green) QAS vitamin K registry. http://www.pkdiet.com/pdf/vit/vitkreg.pdf. Last accessed September 27, 2016 Warfarin Other factors that can affect INR Activity level Bowel habits Fluid status Smoking Patient case It’s the year 2009… ML is a 64-year-old male with history of hypertension who is seen in the emergency department (ED) for increased shortness of breath. He is diagnosed with 6 pulmonary emboli (PE). He is started on enoxaparin (Lovenox®) 1 mg/kg BID in the ED, and needs to be discharged on an oral medication. How would this patient’s PE be managed? Patient case • Patient would be started on warfarin for outpatient anticoagulation for PE • What dose of warfarin would you start the patient on? • Would you continue the enoxaparin? • If yes, for how long? Warfarin initiation • CHEST guidelines: 10 mg x 2 days then 5 mg daily for “healthy” patients • Elliot protocol: • Start patients on 5 mg daily • Initiate patients on 2.5 mg if patient is elderly, under 50 kg, or on severely interacting medications Patient case • What dose of warfarin would you start the patient on? • 5 mg daily • Would you continue the enoxaparin? • Yes • If yes, for how long? • Until INR is over 2.0, or for 5 days total • Subsequent warfarin daily dosing will depend on INR results Patient case • ML is discharged from the hospital on Lovenox 1 mg/kg BID and warfarin 5 mg daily • He is referred to the Anticoagulation clinic for further management Anticoagulation clinics-The past • Point of care testing • Warfarin dosing per protocol • Patient assessment • Initial and ongoing education • Over the phone management: • PT/INR laboratory monitoring • Visiting nurse point of care testing • Patient home testing Patient case It’s the year 2016… ML is a 64-year-old male with history of hypertension who is seen in the emergency department (ED) for increased shortness of breath. He is diagnosed with 6 pulmonary emboli (PE). He needs to be started on an oral anticoagulant. How would this patient’s PE be managed in the present day? Current oral anticoagulants • Warfarin (Jantoven®, Coumadin®) • Dabigatran (Pradaxa®) • Rivaroxaban (Xarelto®) • Apixaban (Eliquis®) • Edoxaban (Savaysa®) DOACs NOACs TSOACs DOACS/NOACs/TSOACs • DOAC = Direct-acting oral anticoagulant • NOAC = Novel oral anticoagulant • NOAC = New oral anticoagulant • NOAC = Non-vitamin K antagonist oral anticoagulant • NOAC = Non-vitamin K oral anticoagulant • TSOAC= Target-specific oral anticoagulant NOACs • Dabigatran (Pradaxa®) • Rivaroxaban (Xarelto®) • Apixaban (Eliquis®) • Edoxaban (Savaysa®) Dabigatran • Brand name: Pradaxa • Approved: 2010 (non-valvular atrial fibrillation); expanded in 2014 (VTE treatment) • Pivotal trial • RE-LY • Randomized Evaluation of Long-Term Anticoagulation Therapy • Dabigatran low-dose non-inferior to warfarin for stroke prevention; high-dose superior to warfarin; similar bleeding rates • RELY-ABLE continuation study Wolowacz SE, Roskell NS, Plumb JM, et al. Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty: A meta-analysis. Thromb Haemost 2009;101(1):77-85. Dabigatran Mechanism of action: Direct thrombin inhibitor that inhibits both free and clot-bound thrombin Dabigatran pharmacokinetics • Absorption: • Pro-drug • Bioavailability is only 3-7% • Distribution: • Only 35% protein bound • Metabolism: • Substrate of P-glycoprotein (P-gp) • Active metabolites • Elimination: • Primarily excreted in the urine • Half-life 12-17 hours Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Dabigatran • Available strengths: 75 mg and 150 mg capsules • 110 mg capsule available in Europe and Canada • Atrial fibrillation dosing: • • • • Creatinine clearance (CrCl) more than 30 ml/min:150 mg po twice daily CrCl 15-30 ml/min: 75 mg po twice daily CrCl less than 15 ml/min: not recommended CrCl 30-50 ml/min with co-administration of P-gp inhibitor: 75 mg po twice daily • CrCl less than 30 ml/min: Avoid co-administration • VTE dosing is the same • Beers criteria recommends against using in patients over age 75 Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Creatinine clearance • Estimation of renal function • Used for drug dosing adjustment • Cockcroft-gault equation: • CrCl = [(140 - age) x weight*] / (Scr^ x 72) (x 0.85 for females) *Weight: Use IBW (ideal body weight) • Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet. • Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet. • If ABW (actual body weight) is less than the IBW use ABW • Use adjusted body weight (AjBW) if patient obese • AjBW = IBW + 0.4 (ABW – IBW) ^SCr = serum creatinine Creatinine clearance calculator • http://www.glob alrph.com/multi ple_crcl_2012.ht m True or False • Dabigatran can be put in a weekly medi-planner with a patient’s other medications FALSE!!!! Dabigatran requires special storage… Dabigatran • Storage: • Must remain in original packaging • Use within 4 months of opening container • Administration: • Take with or without food • Swallow capsules wholes • Pregnancy/Breastfeeding • Pregnancy Category C • Breastfeeding risk unknown Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Dabigatran • Lab monitoring • No routine anticoagulation monitoring required • Can prolong aPTT and ECT • Monitor serum creatinine and adjust doses as necessary Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Dabigatran adverse effects • Common (greater than 10%) • Bleeding • Infrequent (1-10%) • • • • • GI bleeding Edema Dyspepsia Pruritus Rash Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Dabigatran reversal • Idarucizumab (Praxbind®) • Humanized monoclonal antibody that binds to dabigatran and its metabolites • 5 mg IV (provided as 2.5 mg/50 ml) Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Dabigatran reversal Moderate bleeding Symptomatic treatment Fluid replacement Mechanical compressions Blood product transfusion Consider FFP Urgent reversal *Severe/major bleeding * Life threatening hemorrhage *Urgent surgery required Praxbind ® 2.5 grams x 2 doses OR 3F-PCC (Profilnine®) and 1-2 units of FFP Dabigatran interruption Renal Function Low bleeding risk High bleeding risk Resumption- Resumptionlow bleeding high risk bleeding risk CrCl greater than 50 ml/min Last dose 2 days before procedure Last dose 3 days before procedure Day after procedure 2-3 days after procedure CrCl 30-50 ml/min Last dose 3 days before procedure Last dose 4-5 days before procedure Day after procedure 2-3 days after procedure Management of anticoagulation in the per-procedural period. http://qio.ipro.org/wpcontent/uploads/2015/10/AQIN_MAP_5-1-2014.pdf Last accessed September 27, 2016 Dabigatran drug interactions • P-gp inducers • P-gp inhibitors • Medications that increase bleeding risk Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. P-gp inducers P-gp inducers Avasimibe Carbamazepine Phenobarbital (primidone) Phenytoin (fosphenytoin) Rifampin St. John’s wort Tipranavir/ritonavir Drug development and drug interactions: table of substrates, inhibitors, and inducers. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664 .htm. Last accessed September 27, 2016 P-gp inhibitors P-gp Inhibitors Amiodarone Macrolides (azithromycin, clarithromycin, erythromycin, telithromycin) Cycylosporine CCB (diltiazem, felodipine, nifedipine, verapamil) PPIs ((lansoprazole, omeprazole, pantoprazole) Dronaderone Ranolazine Grapefruit juice Quinidine Ketoconazole (and other anti-fungal) Saquinavir Lopinavir Statins (atorvastatin, lovastatin, simvastatin Drug development and drug interactions: table of substrates, inhibitors, and inducers. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664 .htm. Last accessed September 27, 2016 Dabigatran drug interactions Medications that increase bleeding risk Aspirin Anti-platelets NSAIDs SSRIs SNRIs Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Dabigatran dietary considerations • Avoid grapefruit juice • Limit alcohol intake Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Rivaroxaban • Brand name: Xarelto ® • Approved in 2011 (non-valvular atrial fibrillation, VTE prophylaxis) and expanded in 2012 (VTE treatment) • Pivotal trial • ROCKET-AF • Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation • Rivaroxaban non-inferior to warfarin in preventing stroke or systemic embolism with less bleeding Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. NEJM. 2011 Sep 8;365(10):883-91 Rivaroxaban • Mechanism of action: factor Xa inhibitor Rivaroxaban pharmacokinetics • Absorption • Bioavailability 80-100% for 10 mg dose with or without food • 15-20 mg dosage should be taken with food to increase bioavailability • Distribution • 92-95% protein bound • Metabolism • CYP 3A4 and P-gp substrate • Elimination • 35% excreted unchanged in urine • Half life 5-9 hours (11-13 hours in elderly) Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Rivaroxaban • Available strengths: 10 mg, 15 mg, 20 mg • Atrial fibrillation dosing: 20 mg daily with evening meal • CrCl 15-50 ml/min: 15 mg daily with evening meal • CrCl less than 15 ml/min: avoid use • VTE treatment: 15 mg BID with food for 21 days, then 20 mg daily with evening meal • 20 mg daily with evening meal for extended VTE treatment • CrCl less than 30 ml/min: avoid use • VTE prophylaxis: 10 mg daily for 12 days post knee surgery or 35 days post hip surgery • CrCl less than 30 ml/min: avoid use Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Rivaroxaban • Special instructions: • Do not administer to patients receiving a combined P-gp and moderate 3A4 inhibitor (if CrCl 15-80 ml/min) • Administration: • 10 mg with or without food; 15 and 20 mg with evening meal • Tablets can be crushed (crushed tablets stable up to 4 hours) • Pregnancy/Breastfeeding: • Pregnancy category C • Not recommended with breastfeeding Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Rivaroxaban • Lab monitoring: • No routine anticoagulation monitoring required • Can affect INR • Anti-FXa • Monitor serum creatinine and adjust doses as necessary Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Rivaroxaban adverse effects • Infrequent (1-10%) • • • • • Bleeding (including GI bleeding) Back pain Dyspepsia Muscle cramps Pruritus Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Rivaroxaban reversal Moderate bleeding Symptomatic treatment Fluid replacement Mechanical compressions Blood product transfusion Consider FFP Urgent reversal *Severe/major bleeding * Life threatening hemorrhage *Urgent surgery required 3F-PCC (Profilnine®) and 1-2 units of FFP Rivaroxaban reversal • Andexanet alfa (AndexXa®) • Recombinant modified human factor Xa decoy protein (intravenous injection) • Decreases anti-Xa activity by 89% • Not FDA approved yet as of 9/2016 Rivaroxaban interruption Renal Function Low bleeding risk High bleeding risk Resumption- Resumptionlow bleeding high risk bleeding risk CrCl greater than 50 ml/min Last dose 2 days before procedure Last dose 3 days before procedure Day after procedure 2-3 days after procedure CrCl 30-50 ml/min Last dose 2 days before procedure Last dose 3 days before procedure Day after procedure 2-3 days after procedure CrCl 15-29 ml/min Last dose 3 days before procedure Last dose 4 days before procedure Day after procedure 2-3 days after procedure Management of anticoagulation in the per-procedural period. http://qio.ipro.org/wpcontent/uploads/2015/10/AQIN_MAP_5-1-2014.pdf Last accessed September 27, 2016 Rivaroxaban drug interactions • P-gp substrate • P-gp inhibitors and inducers • See dabigatran tables • 3A4 substrate • 3A4 inhibitors • 3A4 inducers • Medications that increase bleeding risk • See dabigatran table Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. 3A4 inhibitors Strong 3A4 inhibitors Boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole Moderate 3A4 inhibitors Amprenavir, aprepitant, atazanavir, ciprofloxacin, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, verapamil Mild 3A4 inhibitors Alprazolam, amiodarone, amlodipine, atorvastatin, bicalutamide, cilostazol, cimetidine, cyclosporine, fluoxetine, fluvoxamine, ginkgo,(5) goldenseal,(5) isoniazid, nilotinib, oral contraceptives, ranitidine, ranolazine, tipranavir/ritonavir, zileuton Drug development and drug interactions: table of substrates, inhibitors, and inducers. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664 .htm. Last accessed September 27, 2016 3A4 inducers Strong 3A4 inducers Moderate 3A4 inducers Avasimibe, Bosentan, efavirenz, carbamazepine, etravirine, modafinil, phenytoin, rifampin, St. nafcillin John’s wort Mild 3A4 incuders Amprenavir, aprepitant, armodafinil, echinacea,pioglitazone, prednisone, rufinamide Drug development and drug interactions: table of substrates, inhibitors, and inducers. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664 .htm. Last accessed September 27, 2016 Rivaroxaban dietary considerations • Avoid grapefruit juice • Take 15 mg and 20 mg dosages with food • Limit alcohol intake Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Apixaban • Brand name: Eliquis ® • Approved: 2014 (non-valvular atrial fibrillation, VTE prophylaxis, VTE treatment) • Pivotal trial: • ARISTOTLE • Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation • Apixaban superior to warfarin in preventing stroke and systemic embolism with less intracranial bleeding (similar GI bleeding rates) Granger CB, Alexander JH, McMurray JJV et al. “Apixaban versus Warfarin in Patients with Atrial Fibrillation”. NEJM. 2011; 365:981-992 Apixaban • Mechanism of action: factor Xa inhibitor Apixaban pharmacokinetics • Absorption • Bioavailability 50 % • Absorption not affected by food • Distribution • Protein binding 87% • Metabolism • Metabolized by CYP-3A4 • Also a substrate of P-gp • No active metabolites • Elimination • Some urine and fecal Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Apixaban • Available strengths: 2.5 mg, 5 mg • VTE dosing: • 10 mg (2 of the 5 mg tablets) twice daily x 7 days, then 5 mg twice daily • VTE prophylaxis following treatment: • 2.5 mg twice daily • VTE prophylaxis knee and hip surgery: • Knee: 2.5 mg twice daily for 12 days starting 12-24 hours post surgery • Hip: 2.5 mg twice daily for 35 days starting 12-24 hours post surgery • Atrial fibrillation: • 5 mg twice daily • 2.5 mg twice daily if age 80 or greater, serum creatinine 1.5 or greater, body weight 60 kg or less Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Apixaban • Administration: • With or without food • NPO (nothing by mouth): Crush and suspend the tablet in 60 ml 5% dextrose solution; administer immediately through a nasogastric tube (no data for oral administration of suspension) • Pregnancy/Breastfeeding: • Pregnancy category B (increased risk of maternal bleeding in rats) • Not recommended in breast-feeding Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Apixaban • Lab monitoring: • No routine anticoagulation lab monitoring required • Anti-factor Xa activity • Can also affect INR • Monitor serum creatinine and adjust doses as necessary Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Apixaban adverse effects • Infrequent (1-10%) • Bleeding • • • • • Epistaxis Hematoma Hematuria Hemoptysis Vaginal bleeding • Anemia Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Apixaban reversal Moderate bleeding Symptomatic treatment Fluid replacement Mechanical compressions Blood product transfusion Consider FFP Urgent reversal *Severe/major bleeding * Life threatening hemorrhage *Urgent surgery required 3F-PCC (Profilnine®) and 1-2 units of FFP Apixaban reversal • Andexanet alfa (AndexXa®) • Recombinant modified human factor Xa decoy protein (intravenous injection) • Decreases anti-Xa activity by 93% • Not FDA approved yet as of 9/2016 Apixaban interruption Renal Function Low bleeding risk High bleeding risk Resumption- Resumptionlow bleeding high risk bleeding risk CrCl greater than 50 ml/min Last dose 2 days before procedure Last dose 3 days before procedure Day after procedure 2-3 days after procedure CrCl 30-50 ml/min Last dose 3 days before procedure Last dose 4 days before procedure Day after procedure 2-3 days after procedure Management of anticoagulation in the per-procedural period. http://qio.ipro.org/wpcontent/uploads/2015/10/AQIN_MAP_5-1-2014.pdf Last accessed September 27, 2016 Apixaban drug interactions • P-gp substrate • P-gp inhibitors and inducers • See dabigatran list • 3A4 substrate • 3A4 inhibitors and inducers • See rivaroxaban list • Medications that increase bleeding risk Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Apixaban dietary considerations • Avoid grapefruit juice • Limit alcohol intake Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Edoxaban • Brand name: Savaysa ® • Approved: 2015 for non-valvular atrial fibrillation and VTE • Pivotal trial • ENGAGE AF-TIMI 48 • The Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 • Non-inferior to warfarin with less major bleeding and intracranial bleeding (more GI bleeding with higher dose) Giugliano RP, Ruff CT, Braunwald E et al. “Edoxaban versus Warfarin in Patients with Atrial Fibrillation”. NEJM. 2013; 369:2093-2104 Edoxaban • Mechanism of action: factor Xa inhibitor Edoxaban pharmacokinetics • Absorption • Bioavailability 62%, not affected by food • Distribution • Low protein binding • Metabolism • Minimally metabolized by CYP 3A4 • P-gp substrate • Elimination • Primarily excreted unchanged in urine Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Edoxaban • Available strengths: 15 mg, 30 mg, 60 mg • Non-valvular atrial fibrillation dosing: • CrCl 51-94 ml/min: 60 mg daily • CrCl 15-50 ml/min: 30 mg daily • CrCl over 95 ml/min: DO NOT USE • VTE treatment: • Greater than 60 kg: 60 mg daily following 5-10 days of initial treatment with parenteral anticoagulant • Less than 60 kg: 30 mg daily following 5-10 days of initial treatment with parenteral anticoagulant Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Edoxaban • Administration: • May be taken with or without food • Pregnancy/Breastfeeding: • Pregnancy category C • Breastfeeding: unknown effects Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Edoxaban • Lab monitoring: • No routine anticoagulation monitoring required • Can prolong PT/INR and aPTT • Anti-FXa activity • Monitor serum creatinine and adjust doses as necessary Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Edoxaban adverse effects • Infrequent (1-10%) • Bleeding • • • • Epistaxis GI bleeding Hematuria Vaginal bleeding • Anemia • Elevated hepatic enzymes • Rash Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Edoxaban reversal Moderate bleeding Symptomatic treatment Fluid replacement Mechanical compressions Blood product transfusion Consider FFP Urgent reversal *Severe/major bleeding * Life threatening hemorrhage *Urgent surgery required 3F-PCC (Profilnine®) and 1-2 units of FFP Edoxaban reversal • Aripazine (aka ciraparantag and PER977) • Cationic molecule designed to bind specifically to novel oral anticoagulants • Currently in clinical trials (FDA fast track in 2015) Edoxaban interruption Renal Function Low bleeding risk High bleeding risk Resumption- Resumptionlow bleeding high risk bleeding risk CrCl greater than 50 ml/min Last dose 2 days before procedure Last dose 3 days before procedure Day after procedure Management of anticoagulation in the per-procedural periodhttp://qio.ipro.org/wpcontent/uploads/2015/10/AQIN_MAP_5-1-2014.pdf Last accessed September 27, 2016 2-3 days after procedure Edoxaban drug interactions • P-gp inhibitors and inducers • See dabigatran table • Drugs that increase risk of bleeding: • Aspirin • Anti-platelets • NSAIDs Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Edoxaban dietary considerations • Avoid grapefruit juice • Limit alcohol intake Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Anticoagulant comparison Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Generic Yes No No No No Average cost per month* $10.72 $340.20 $344.60 $346.01 $292.61 FDA approval date Pre-1982 October 2010 July 2011 Dec 2012 Jan 2015 FDA approved indications AF (w/ valves) AF (no valves) VTE treatment VTE treatment & prophylaxis AF (no valves) VTE treatment & prophylaxis AF (no valves) VTE treatment & prophylaxis AF (no valves) VTE treatment & prophylaxis Dosage Variable 75 or 150 mg 10, 15, 20 mg 2.5 or 5 mg 30, 60 mg Dosage frequency Daily BID Daily (BID loading dose VTE) BID Daily Onset Slow Rapid Rapid Rapid Rapid *Average cost per insurance claim made. https://masshealthdruglist.ehs.state.ma.us/MHDL/pubtheradetail.do?id=110 Last accessed September 28, 2016 Anticoagulant comparison Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Kidney function No Yes (kidney function affects dose) Yes (kidney function affects dose) Yes (kidney function affects dose) Yes (kidney function affects dose) Pregnancy/bre astfeeding Preg: X BF: Yes Preg: C BF: No Preg: C BF: No Preg: B BF: No Preg: C BF: No Drug interactions Many Some Some Some Some Dietary interactions Yes, many GFJ ETOH GFJ ETOH GFJ ETOH GFJ ETOH Lab monitoring (anticoag) Yes No No No No Reversal Vitamin K PCC and FFP Praxbind PCC and FFP PCC and FFP PCC and FFP PCC and FFP Patient case It’s the year 2016… ML is a 64-year-old male with history of hypertension who is seen in the emergency department (ED) for increased shortness of breath. He is diagnosed with 6 pulmonary emboli (PE). He needs to be started on an oral anticoagulant. How would this patient’s PE be managed in the present day? Current oral anticoagulants • Warfarin (Jantoven®, Coumadin®) • Dabigatran (Pradaxa®) • Rivaroxaban (Xarelto®) • Apixaban (Eliquis®) • Edoxaban (Savaysa®) Chest guidelines • CHEST guidelines VTE 2016 update • In patients with DVT of the leg or PE and no cancer, as long-term (first 3 months) anticoagulant therapy, we suggest dabigatran, rivaroxaban, apixaban, or edoxaban over vitamin K antagonist (VKA) therapy (warfarin) • Initial parenteral anticoagulation is given before dabigatran and edoxaban, is not given before rivaroxaban and apixaban, and is overlapped with VKA therapy. • In patients with DVT of the leg or PE who receive extended therapy, we suggest that there is no need to change the choice of anticoagulant after the first 3 months Kearon C, Akl EA, Ornelas J et al. “Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report”. Chest. 2016;149(2):315-352 Patient case • ML was started on Xarelto® (rivaroxaban) 15 mg po BID with food x 21 days then transitioned to 20 mg daily • He was not referred to an anticoagulation clinic and was given minimal education on his new high-risk medication Anticoagulation clinics-The Present • Point of care testing/over the phone management • Warfarin dosing per protocol • Patient assessment • Initial and ongoing warfarin education • Enoxaparin bridging recommendations • Support for switching between warfarin and NOACs Switching therapies Switching from dabigatran to warfarin: Creatinine clearance Instructions CrCl greater than 50 ml/min Start warfarin 3 days before discontinuing dabigatran CrCl 31-50 ml/min Start warfarin 2 days before discontinuing dabigatran CrCl 15-30 ml/min Start warfarin 1 day before discontinuing dabigatran Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Switching therapies Switching from warfarin to dabigatran: • Discontinue warfarin and wait until INR is less than 2.0, then start dabigatran as follows: Creatinine clearance Dabigatran dosing CrCl greater than 30 ml/min 150 mg twice daily CrCl 15-30 ml/min 75 mg twice daily CrCl less than 15 ml/min Not recommended Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Switching therapies Switching from rivaroxaban to warfarin: • Stop rivaroxaban and administer LMWH + warfarin when next dose of rivaroxaban was due (rivaroxaban can affect INR) • Continue LMWH until INR is over 2.0 Switching from warfarin to rivaroxaban: • Stop warfarin and start rivaroxaban once INR is less than 3.0 Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Switching therapies Switching from apixaban to warfarin: • If continuous anticoagulation is needed, discontinue apixaban and start warfarin + LMWH until INR therapeutic (apixaban can affect INR) Switching from warfarin to apixaban: • Discontinue warfarin and start apixaban when INR is less than 2.0 Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Switching therapies • Switching from edoxaban to warfarin: • For patients taking edoxaban 60 mg daily, decrease dosage to 30 mg daily and start warfarin; discontinue edoxaban when INR is over 2.0 • For patients taking edoxaban 30 mg daily, decrease dosage to 15 mg daily and start warfarin; discontinue edoxaban when INR is over 2.0 • Switching from warfarin to edoxaban: • Stop warfarin and start edoxaban when INR is less than 2.5 Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Savaysa® patient package insert. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf Last accessed September 28, 2016 Patient case • ML continues on Xarelto 20 mg daily • He has received minimal education from his physician’s office regarding this high risk medication • How can anticoagulation clinics help patients like ML? Anticoagulation Clinics: The Future For patients taking warfarin seen in office*: • Assess compliance • Deliver patient education • Evaluate for diet and drug interactions • Assess for falls, bleeding or clotting adverse effects • Reduce risk of complications associated with anticoagulation therapy • POC INR and adjust dose as appropriate • Set up follow-up appointment *Same for phone managed patients, minus POC testing Anticoagulation Clinics: The Future For patients taking NOACs seen in the office: • Assess compliance • Deliver patient education • Evaluate for diet and drug interactions • Assess for falls, bleeding or clotting adverse effects • Evaluate serum creatinine, CrCl, liver function and hemoglobin • Establish appropriate dose and make adjustments when needed • Reduce risk of complications associated with anticoagulation therapy Anticoagulation clinics How can we make the future start now? • Billing • Expansion of protocols • Pilot program Conclusion • Coagulation is a complicated process, and anticoagulation therapy can also be complex • There are several indications for anticoagulation therapy • Anticoagulants are high-risk medications, and they require close monitoring and patient education to ensure proper usage • There are currently five oral anticoagulants available • Anticoagulation clinics should consider expanding beyond patients taking warfarin and offer support for patients taking newer anticoagulant agents Questions? Contact info Jill Hiers, Pharm.D., BCPS [email protected] References Blood clotting. http://www.myvmc.com/investigations/blood-clotting-international-normalisedratio-inr/ Last accessed September 27, 2016. CDC data and statistics. http://www.cdc.gov/ncbddd/dvt/data.html. Last accessed September 30, 2016 CHA2DS2-VASc.http://www.mdcalc.com/cha2ds2-vasc-score-for-atrial-fibrillation-stroke-risk/. Last accessed September 27, 2016. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated August 2016. Clotting cascade. http://www.neurology.org/content/78/7/501/F2.large.jpg. Accessed June 21, 2016. Douketis JD, Spyropolous AC, Spencer FA et al. “Perioperative Management of Antithrombotic Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines”. Chest. 2012;141(2_suppl):e326Se350S. references Drug development and drug interactions: table of substrates, inhibitors, and inducers. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteract ionsLabeling/ucm093664.htm. Last accessed September 27, 2016 Garcia and Crowther. Reversal of warfarin. Circulation. 2012;125 (23) Giugliano RP, Ruff CT, Braunwald E et al. “Edoxaban versus Warfarin in Patients with Atrial Fibrillation”. NEJM. 2013; 369:2093-2104 Granger CB, Alexander JH, McMurray JJV et al. “Apixaban versus Warfarin in Patients with Atrial Fibrillation”. NEJM. 2011; 365:981-992 HAS-BLED. http://www.mdcalc.com/has-bled-score-for-major-bleeding-risk/ Last accessed September 27, 2016. High risk medications.http://www.ismp.org/selfassessments/hospital/2011/definitions.pdf. Last accessed September 27, 2016 Holbrook A, Schulman S, Witt D, et al. Evidence Based Management of Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed. American College of Chest Physicians Evidence Based Clinical Practice Guidelines. CHEST. 2012;141:e152s-184s. References Kearon C, Akl EA, Ornelas J et al. “Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report”. Chest. 2016;149(2):315-352 Management of anticoagulation in the per-procedural periodhttp://qio.ipro.org/wpcontent/uploads/2015/10/AQIN_MAP_5-1-2014.pdf Last accessed September 27, 2016 Massachusetts health drug list. https://masshealthdruglist.ehs.state.ma.us/MHDL/pubtheradetail.do?id=110 Last accessed September 28, 2016 National patient safety goals. http://www.jointcommission.org/assets/1/6/2015_NPSG_HAP.pdf. Last accessed September 27, 2016 Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. NEJM. 2011 Sep 8;365(10):883-91 QAS vitamin K registry. http://www.pkdiet.com/pdf/vit/vitkreg.pdf. Last accessed September 27, 2016 References Savaysa® patient package insert. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf Last accessed September 28, 2016 Warfarin https://www.drugs.com/pro/warfarin.html. Last accessed September 27, 2016. Warfarin ambulatory guideline.http://www.uwhealth.org/files/uwhealth/docs/pdf2/Ambulatory_Warfarin_Guideline .pdf Last accessed September 27, 2016 Wolowacz SE, Roskell NS, Plumb JM, et al. Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty: A meta-analysis. Thromb Haemost 2009;101(1):77-85. Young S, Bishop L, Twells L et al. “Comparison of pharmacist managed anticoagulation with usual medical care in a family medicine clinic”. BMC Fam Pract. 2011. 12:88 doi: 10.1186/14712296-12-88