1 Oral Anticoagulants: What s New? Sallie Young, Pharm.D., BCPS (AQ-Cardiology) Clinical Pharmacy Specialist, Cardiology Penn State Hershey Medical Center August 2012
2 Oral Anticoagulant Uses Multiple reasons for oral anticoagulant use VTE prophylaxis Atrial fibrillation/flutter VTE - pulmonary embolism (PE) and/or deep vein thrombosis (DVT) Mechanical heart valves Hypercoagulable states
3 Ideal Characteristics of a New Oral Anticoagulant Multiple indications Oral Once daily dosing No drug interactions No dietary restrictions Antidote availability Inexpensive Predictable response Wide therapeutic window No monitoring required Does not cross placenta or into breast milk
4 Oral Anticoagulation Options Until recently warfarin was only oral anticoagulant available in US Required patient education on Medication and diet consistency Frequency of INR monitoring Use of multiple tablet sizes Alternating doses on different days And much more! Image accessed 3/27/12 from
5 Current Anticoagulation Options Warfarin (Coumadin) Dabigatran (Pradaxa) Approved 2010 Rivaroxaban (Xarelto) Approved 2011 Several others oral anticoagulants are in the later stages of clinical trials Apixaban (Under FDA Review)
6 Clotting Cascade Factor Xa Inhibitors - rivaroxaban Vitamin i K Antagonist (factors 2,7,9, 10, protein c and s) - Warfarin Direct Thrombin Inhibitor - dabigatran
7 Review of Newly Approved Oral Anticoagulants t Dabigatran (Pradaxa ) Rivaroxaban (Xarelto )
8 Dabigatran Etexilate Dabigatran etexilate is a prodrug rapidly converted to the active form, dabigatran, in the body Reversible, direct thrombin inhibitor Inhibits formation of thrombin (factor IIa) therefore preventing formation of fibrin clots Inhibits free and clot bound thrombin as well as thrombin-induced platelet aggregation Lexi-Comp. Accessed 4/6/12.
9 Dabigatran Uses FDA approved indication Reduction in the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillationill i Potential future uses Treatment of venous thromboembolism (VTE, including deep vein thrombosis and pulmonary embolism) Prevention of VTE after orthopedic surgery, such as hip and knee replacement* *Indication in other countries. Lexi-Comp. Accessed 4/6/11.
10 Dabigatran Pharmacokinetics Onset of activity it within 2 hours Low bioavailability (3-7%) Half-life hours No involvement of the CYP450 system however is a p-glycoprotein substrate Cleared renally primarily as glucuronide acid conjugate Prolongs aptt PTTin non-linear fashion Pradaxa Prescribing Information. January 2012.
11 Dabigatran Elimination As renal function declines, the half-life life of the drug increases Renal Function (CrCl) Dabigatran Half Life Normal hours (~80 ml/min) ( hours in elderly) l Mild - Moderate hours impairment (30-50 ml/min) Severe impairment (<30 ml/min) 28 hours Lexi-Comp. Accessed 4/6/12. Stangier et al. Clin Pharmacokinetics 2010;49:
12 Dabigatran AFib Dosing Usual dose: 150 mg orally twice daily Reduce to 75 mg orally twice daily* when CrCl ml/min Consider if CrCl ml/min + p-glycoprotein inhibitors (dronedarone or oral ketoconazole ) Avoid in patients with CCl CrCl <15 ml/min or those on dialysis dil i CrCl ml/min + p-glycoprotein inhibitors *Renal dosing based on pharmacokinetic analysis (not patient data) at time of FDA approval Pradaxa Prescribing Information. January 2012.
13 Dabigatran Monitoring: Routine laboratory testing is not necessary Diet interactions None - vitamin K intake has no effect May be taken with or without food Capsules may not be opened as the drug bioavailability increases by 75%! Should not be administered via feeding tube or with applesauce/pudding Pradaxa Prescribing Information. January 2012.
14 Composition of Dabigatran Dabigatran Etexilate Capsule Capsules Dabigatran Etexilate Pellet Tartaric Acid Core Dabigatran Etexilate Coat Seal Coating Connolly SJ, Ezekowitz MD et al. N Engl J Med. 2009;361: Pradaxa Prescribing Information. Jan 2012.
15 Dabigatran Adverse Effects Bleeding Major bleeding more common than in warfarin patients (1.73% per yr vs. 0.87% per yr) Increased risk as renal function declines Increased gastrointestinal bleeding (dose dependant) d Gastrointestinal upset Incidence higher (35%) than with warfarin (24%) Dyspepsia, abdominal pain, GERD, esophagitis, erosive gastritis, gastrointestinal ulcer Lexi-Comp. Accessed 1/19/11. Connolly SJ et al. N Engl J Med 2010;361:
16 Dabigatran Drug Interactions Does not involve CYP450 enzymes in the liver P-glycoprotein inducers (ex. rifampin) - decrease dabigatran levels/efficacy; PI: Generally Avoid P-glycoprotein inhibitors (ketoconazole, dronedarone) increase dabigatran levels/toxicity Use with other antiplatelet medications, including NSAIDs - increases bleeding risk due to thrombinid induced dplatelet ltltaggregation Should not be used at the same time as warfarin (Coumadin) - therapeutic duplication Lexi-Comp. Accessed 1/19/11.
17 Rivaroxaban (Xarelto) Factor Xa inhibitor Highly selective Exerts activity by blocking the active site on factor Xa Does not require cofactor (such as antithrombin) Inhibits free and clot-associated factor Xa Xarelto Prescribing Information. December 2011.
18 Rivaroxaban Uses FDA Approved Indications Prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in patients who are undergoing knee or hip replacement surgery Prevention of stroke or systemic embolism in nonvalvular atrial fibrillation patients Future Use VTE Treatment (PE, DVT)
19 Rivaroxaban Pharmacokinetics Onset of activity it 2-4 4hours Bioavailability >80% for 10 mg, 66% for 20 mg Food increases bioavailability ( 39% mean AUC) Half-life 5-9 hours (elderly 9-12 hrs) Highly and reversibly bound to plasma proteins Undergoes CYP450 metabolism (3A4/5 and 2J2 substrate) but no circulating metabolites P-glycoprotein and ABCG2 substrate Excreted via renal (66%) and non-renal (28%) mechanisms ACCP CHEST Guidelines 9 th Ed. CHEST 2012;141:e44S-e88S.
20 Rivaroxaban for VTE Prophylaxis Prophylaxis of DVT/PE in adult patients undergoing hip and knee replacement surgery CrCl 30 ml/min: 10 mg PO once daily CrCl<30 ml/min or dialysis: Contraindicated Initial dose should be taken at least 6 to 10 hours after surgery once hemostasis has been established Caution with epidural/spinal anesthesia catheter placement/removal or if traumatic puncture Duration: 35 days after THR, 12 days for TKR Xarelto Prescribing Information. December 2011.
21 Rivaroxaban for Atrial Fibrillation Prevention of stroke or systemic embolism in non-valvular atrial fibrillation patients CrCl >50 ml/min: 20 mg po once daily with the evening meal CrCl ml/min: 15 mg po once daily with the evening meal CrCl<15 ml/min or dialysis: CONTRAINDICATED Xarelto Prescribing Information. December 2011.
22 Rivaroxaban Drug Interactions CYP3A4/P-glycoprotein (P-gp) )inducers AVOID, significant in AUC & Cmax; lower efficacy Examples: carbamazepine, phenytoin, rifampin, St. John's wort CYP3A4/P-gp inhibitors AVOID, significant in AUC & Cmax; toxicity Examples: ketoconazole, itraconazole, ritonavir, conivaptan Concomitant use of antiplatelet agents bleeding time Xarelto Prescribing Information. December 2011.
23 Rivaroxaban ADRs Bleeding Similar incidence of major and nonmajor clinically relevant bleeding to warfarin in ROCKET-AF trial Intracranial hemorrhage 0.8% vs. 1.2% in warfarin group (p=0.02) Critical and fatal bleeding significantly less in rivaroxaban patients Non-bleeding: wound secretion, extremity pain, muscle spasm, syncope, pruritis and blisters Xarelto Prescribing Information. December 2011.
24 Converting to and from new oral anticoagulants
25 General Conversion Thoughts Drug clearance should be taken into consideration Hepatic or renal failure? Risk benefit evaluation Bleeding vs. thromboembolism Administration times? Any dose of dabigatran or rivaroxaban would provide VTE prophylaxis (or more)
26 Dabigatran - Warfarin Warfarin to dabigatran Stop warfarin and start dabigatran when INR <2 Dabigatran to warfarin Before stopping dabigatran, start warfarin CrCl 50 ml/min: 3 days CCl3050 CrCl ml/min: 2 days CrCl ml/min: 1 day CrCl <15 ml/min: no recommendation Only check INR after dabigatran stopped for at least 2 days because may affect result Pradaxa Prescribing Information. Jan Lexi-Comp Online. Accessed 3/29/12
27 Dabigatran Parenteral Anticoagulants Parenteral anticoagulant to dabigatran No bridging therapy necessary due to quick onset Start t dabigatran 2 hours prior to the time of the next scheduled dose of the parenteral anticoagulant (e.g. LMWH) or at the time of discontinuation for a continuously administered parenteral drug (e.g. UFH) Dabigatran to parenteral anticoagulant Wait 12 hours (CrCl 30 ml/minute) or 24 hours (CrCl <30 ml/minute) after the last dose of dabigatran before initiating a parenteral anticoagulant Pradaxa Prescribing Information. Jan Lexi-Comp Online. Accessed 3/29/12
28 Rivaroxaban - Warfarin Warfarin to rivaroxaban Discontinue warfarin and initiate rivaroxaban as soon as INR falls to <3.0 (U.S. labeling) Rivaroxaban to warfarin Initiate warfarin and a parenteral anticoagulant 24 hours after discontinuation of rivaroxaban Rivaroxaban affects INR therefore, initial INR measurements after initiating warfarin may be unreliable Rivaroxaban monograph. Lexi-Comp Online. Accessed 3/29/12
29 Rivaroxaban Parenteral Anticoagulants Parenteral anticoagulant to rivaroxaban No bridging therapy necessary due to quick onset Start t rivaroxaban 2 hours prior to the time of the next scheduled dose of the parenteral anticoagulant (e.g. LMWH) or at the time of discontinuation for a continuously administered parenteral drug (e.g. UFH) Rivaroxaban to parenteral anticoagulant Initiate the anticoagulant 24 hours after discontinuation of rivaroxaban Rivaroxaban monograph. Lexi-Comp Online. Accessed 3/29/12
30 Reversing Oral Anticoagulants
31 Reversal ersal Information No antidote/reversal agent available ***Renal function impacts duration of effect*** Allow appropriate time for drug clearance prior to surgical procedures or epidural/spinal i linjections Symptomatic management for bleeding Fluid replacement, hemodynamic support Start measures to support good renal function (fluids, avoiding nephrotoxins, etc) Dialysis removes up to 60% of dabigatran Rivaroxaban - protein binding so no effect ACCP CHEST Guidelines 9 th Ed. CHEST 2012;141:e44S-e88S.
32 Dabigatran and Surgery Renal function Half-life Timing of discontinuation after last (CrCL, ml/min) (hours) dose of dabigatran before surgery Standard risk of bleeding High risk of bleeding >80 13 (11-22) 24 hours 2-4 days >50 to (12-34) 24 hours 2-4days >30 to (13-23) At least 2 days 4 days (48 hours) 30 c 27 (22-35) 2-5 days >5 days Table modified from: van Ryn J, et al. Thromb Haemost 2010;103:
33 High Risk Surgical Procedures (The small print under the table) Includes when complete hemostasis may be required, for example Cardiac surgery, neurosurgery, abdominal surgery or those involving a major organ Other procedures such as spinal anesthesia may also require complete hemostatic function Also consider advancing age, co morbidities (e.g. major cardiac, respiratory or liver disease) and concomitant use of antiplatelet therapy Modified from: van Ryn J, et al. Thromb Haemost 2010;103:
34 Rivaroxaban and Surgery Renal function (CrCL, ml/min) Half-life (hours) Timing of discontinuation after last dose of rivaroxaban before surgery Standard risk of High risk of bleeding bleeding Normal to mild ~9 hours Hold 2 doses Hold 3-4 doses impairment (CrCl >50 ml/min)
35 Life-Threatening Bleeding LIMITED data available to direct therapy Dabigatran Recombinant factor VIIa FEIBA (activated prothrombin complex concentrates or apcc) CHEST guidelines say only if dilutional coagulopathy Rivaroxaban Recombinant factor VIIa PCC was not effective
36 Patient Counseling Pointers
37 Patient Counseling Activity level recommendations are the same as with warfarin Avoid dangerous activities (no sky diving, caution when icy, etc ) Should be taken at same time of day (every 12 hrs or with evening meal) If dose missed, take it as soon as possible but do not double up
38 Patient Counseling Avoid taking NSAIDS or aspirin unless instructed by their healthcare provider Patient should report any adverse effects to provider (bleeding, GI related) Remind any healthcare provider about use of an anticoagulant prior to procedures (dental, surgical) or spinal/epidural catheter placement/removal
39 Dabigatran Pointers Capsules only good dfor 4 months once bottle is opened Blister packs available Instruct patients to swallow the capsules whole Breaking, chewing, or emptying the contents of the capsule can result in increased exposure =3632. Assessed 3/27/12.
40 Rivaroxaban Pointers 10, 15 and 20 mg tablets available 10 and 15 mg tablets are round 20 mg tablets are triangular None are scored Tablets may be crushed and administered via gastric feeding tube May not be given via a NJ, J-tube or GJ tube Xarelto Prescribing Information. December 2011.
41 Important Considerations for Use of New Oral Anticoagulants Much more expensive than warfarin Often patients have much higher insurance copay Compliant patient? Twice daily dosing required for dabigatran Missed doses increase risk of thromboembolism Bleeding risk? No reversal agent is available if bleeding occurs or emergent procedure necessary Mechanical heart valve? Not studied yet
42 Patients in Whom to Consider Use of New Oral Anticoagulants Allergy/intolerance to warfarin Trouble maintaining therapeutic INRs Those without access to monitoring Patients without significant ifi renal or hepatic impairment Patients not on interacting medications Able to be compliant with medications
43 To Wrap It All Up... The new oral anticoagulants are good alternatives to warfarin for patients who need anticoagulation As more agents gain FDA approval, increased use expected Pharmacists will have large role in choice of agents, dosing, adjustment for other disease states, drug interactions & patient education