1 New Oral Anticoagulants: Thinning out the competition Ashlee D. Gerfen, Pharm.D. University of Arizona Medical Center PGY2 Critical Care Pharmacy Resident
2 DISCLOSURE I have no financial interest, arrangement, or affiliation that would constitute a conflict of interest
3 OBJECTIVES Compare pharmacology, pharmacokinetics, and pharmacodynamics characteristics, and other attributes of new anticoagulants Identify patient care issues revolving new oral anticoagulant agents Select most appropriate oral anticoagulant agent using evidence based medicine for individual patients
4 ATRIAL FIBRILLATION AND RISK OF STROKE Evidence-based guidelines recommend use of oral anticoagulant or antiplatelet therapy to reduce the incidence of stroke in patients with AF, regardless of the method used to manage arrhythmia Warfarin reduces risk of stroke by 64% Aspirin reduces risk of stroke by 19% Camm. J Intern Med 2012.
5 Stroke Rate % THROMBOSIS RISK ASSESSMENT: CHADS 2 SCORE Risk Factor Score C = CHF 1 H = hypertension 1 A = age 75 years 1 D = DM 1 S 2 = hx of stroke or TIA 2 TOTAL 6 Stroke Risk with CHAD 2 Score 20.00% 18.2% 18.00% 16.00% 14.00% 12.5% 12.00% 10.00% 8.5% 8.00% 5.9% 6.00% 4% 4.00% 1.9% 2.8% 2.00% 0.00% CHADS 2 Score Gage. JAMA 2001.
6 Stroke Rate % THROMBOSIS RISK ASSESMENT: CHA 2 DS 2 - VASc SCORE Risk Factor Score C = CHF 1 H = hypertension 1 A 2 = age 75 years 2 D = DM 1 S 2 = hx of stroke or TIA 2 V = vascular disease 1 A = age years 1 Sc = Sex category 1 TOTAL 9 Stroke Risk with CHA 2 DS 2 -VASc Score [VALUE]% 10.1% % 4.7% 5 3.9% 2.3% 1.9% 0.7% 0% 0 CHADS 2 Score [VALUE]% Gage. JAMA 2001., Lip. CHEST 2010.
7 HAS-BLED SCORE Category Score H = HTN (SBP > 160) 1 A = Abnormal renal and liver fx - chronic HD, renal txp, SCr 2.26 mg/dl - Chronic hepatic dz, bilirubin > 2x UNL in association with AST/ALT/Alk Phos > 3x UNL S = Stroke 1 B = Bleeding (hx or predisposition such as anemia) L = Labile INRS (unstable/high, time in therapeutic range < 60%) E = Elderly (>65 yrs old) 1 D = Drugs or alcohol - Antiplatelet or NSAIDs 1 or 2 (1 point each) or 2 (1 point each) Pisters. Chest 2010.
8 HAS-BLED SCORE Predictive accuracy consistent in overall population using significant risk factors Score 3 = high risk bleed Pisters. Chest 2010.
9 ANTICOAGULATION GUIDELINES ACCF/AHA/HRS CCS ESC CHADS 2 = 0 Aspirin Aspirin or none Evaluate further with CHA 2 DS 2 VASc score, none or aspirin CHADS 2 = 1 Aspirin or Dabigatran/Warfarin Aspirin or Dabigatran*/Warfarin Evaluate further with CHA 2 DS 2 VASc score CHADS 2 2 Dabigatran/Warfarin Dabigatran*/Warfarin Anticoagulation CHA 2 DS 2 VASc Not used Not used 0 = none 1 = anticoagulation or none > 1 = anticoagulation * Dabigatran preferred over warfarin Wann. Circulation 2011., Gillis. Can J Cardiol 2011., European Heart Rhythm Assoc. European Heart J 2010.
10 FUTURE OF WARFARIN? >50 years, the vitamin K antagonist was the only available oral anticoagulant (OA) Safety, compliance, efficacy all effected by its narrow therapeutic index, often complex dosing regimens, and rigorous monitoring Optimal anticoagulation also complicated by long half life, slow onset of action, and multiple drug/food interactions This shortcomings have prompted development of new OA s Gonsalves. Mayo Clinic 2013.
11 THE IDEAL ANTICOAGULANT Oral, fixed once daily dosing Rapid onset No renal/hepatic adjustments No drug-drug interactions Predictable 1 st order pharmacokinetics/dynamics Wide therapeutic window No routine anticoagulant effect monitoring Limited drug/food interactions Available antidote Reasonable cost
12 NEW ORAL ANTICOAGULANTS Dabigatran Rivaroxaban Apixaban Mechanism Direct IIa inhibitor Direct Xa inhibitor Direct Xa inhibitor Brand Name Pradaxa Xarelto Eliquis Approval Status in US 10/2010: approved by FDA for stroke prevention in AF 7/2011: approved by FDA for VTE ppx in ortho surgery and DVT/PE tx 12/2012: approved by FDA for stroke prevention in AF 11/2011: approved by FDA for stroke prevention in AF Gonsalves. Mayo Clinic 2013.
13 REVIEW OF CLOT FORMATION Di Nisio. N Engl J Med 2005.
14 MECHANISM OF ACTION OF NEW OA s Smythe. Pharmacotherapy 2013.
15 COMPARATIVE PROPERTIES OF OA s Warfarin Dabigatran Rivaroxaban Apixaban Prodrug No Yes No No Bioavailability (%) >95 65 >80 50 Protein binding (%) T 1/2 40 hrs hrs 5-9 hrs, 9-13 hrs hrs Peak effect hrs 2 hrs 2-4 hrs 3-4 hrs Hepatic met Yes No Yes Yes Renal elimination 92% (metabolites) 80% 66% 27% Renal dosing No Yes Yes No? Dialyzable No Yes No No Drug Interactions CYP 2C9, 1A2, 3A4 P-gp inducer/inhibitor CYP3A4 CYP3A4, P-gp inducer/inhibitor Monitoring INR None needed None needed None needed Antidote Vitamin K None None None Gonsalves. Mayo Clinic 2013.
16 CASE #1 A patient has recently diagnosed atrial fibrillation and is currently on dronadrerone therapy. The last CrCl of the patient was calculated at 25 ml/hr. Which of the following medications would be contraindicated for use of atrial fibrillation stroke prevention? A. Rivaroxaban B. Dabigatran C. Apixaban D. Warfarin
17 DABIGATRAN Brand Name: Pradaxa 1 st oral direct thrombin inhibitor approved by FDA Prodrug, rapidly converted to active compound by esterases in plasma and liver MOA: active compound competitively and reversibly binds to active side of free and clotbound thrombin, blocking its procoagulant activity Gonsalves. Mayo Clinic 2013.
18 DABIGATRAN- MOA Di Nisio. N Engl J Med 2005.
19 DABIGATRAN PK/PD Supplied: 75 mg or 150 mg capsules Absorption: Bioavailability with oral is 3 7 % by 75% when pellets are taken without capsule Capsule have tartaric acid core to absorption Should NOT be broke, chewed, or opened Dabigatran etexilate is a substrate of the efflux transport P-gp High-fat meals delays time to C max by 2 hours (no effect of bioavailability) Can be administered with or without food Pradaxa. PI 2010.
20 DABIGATRAN PK/PD Distribution: 35% bound to plasma proteins Metabolism: Prodrug that is converted from dabigatran etexilate to active dabigatran Elimination: Primarily renal (80%), T 1/2 = hrs DDI: P-gp inducers (rifampin), P-gp inhibitors (ketoconazole, verapamil, amiodarone, dronedarone) Pradaxa. PI 2010.
21 DABIGATRAN PK/PD Estimated PK parameters by renal function Renal Function CrCl (ml/min) In AUC In Cmax T 1/2 (hr) Normal 80 1x 1x 13 Mild x 1.1x 15 Moderate x 1.7x 18 Severe* <30 6.3x 2.1x ml/min on HD with 50 mg dose *Pts with CrCl < 30 should avoid concurrent use of P-gp inhibitors 34.1 (62-68% removed by HD) Pradaxa. PI 2010., Stangier. Clin Pharmacokinetics 2010.
22 DABIGATRAN - INDICATIONS FDA approved indication: Prevention of stroke and systemic embolism in nonvalvular Atrial Fibrillation Dose: CrCl > 30 ml/min: 150 mg BID CrCl ml/min: 75 mg BID CrCl < 15 ml/min or dialysis: no recommendations Pradaxa. PI 2010.
23 DABIGATRAN - LITERATURE Indication Trial Name Stroke prevention in AF RE-LY Acute VTE RE-COVER VTE ppx in TKA VTE ppx in THA RE-MODEL RE-MOBILIZE RE-NOVATE I RE-NOVATE II
24 DABIGATRAN - LITERATURE Indication Trial Name Stroke prevention in AF RE-LY Acute VTE RE-COVER VTE ppx in TKA VTE ppx in THA RE-MODEL RE-MOBILIZE RE-NOVATE I RE-NOVATE II
25 DABIGATRAN RE-LY TRIAL Atrial Fibrillation 1 risk factor 951 centers in 44 countries N = 18, 113 Warfarin dose adjusted (INR 2-3) N = 6022 Open Blinded Dabigatran Etexilate 110mg BID N = 6015 Dabigatran Etexilate 150mg BID N = 6076 Inclusion criteria: EKG documented AF and at least one of the following: previous stroke or TIA, left ventricular EF < 40%, NYHA class II or higher heartfailure sx, age of at least 75 yrs or age of yrs + DM, HTN or CAD. Connolly. N Engl J Med 2009.
26 DABIGATRAN RE-LY TRIAL Event Warfarin (% per yr) Dabigatran 110 mg (% per yr) Stroke or systemic embolism Stroke Hemorrhagic Ischemic * 1.11* Dabigatran 150 mg (% per yr) 1.01* 0.10* 0.92* Mortality Major bleed * 3.11 *statistically significant (p < 0.05) 64% Time-in range for warfarin (INR 2-3) Connolly. N Engl J Med 2009.
27 DABIGATRAN RE-LY TRIAL Event Warfarin (% per yr) Dabigatran 110 mg (% per yr) Stroke or systemic embolism Stroke Hemorrhagic Ischemic * 1.11* Dabigatran 150 mg (% per yr) 1.01* 0.10* 0.92* Mortality Major bleed * 3.11 *statistically significant (p < 0.05) 64% Time-in range for warfarin (INR 2-3) Connolly. N Engl J Med 2009.
28 DABIGATRAN RE-LY TRIAL Event Warfarin (% per yr) Dabigatran 110 mg (% per yr) Stroke or systemic embolism Stroke Hemorrhagic Ischemic * 1.11* Dabigatran 150 mg (% per yr) 1.01* 0.10* 0.92* Mortality Major bleed * 3.11 *statistically significant (p < 0.05) 64% Time-in range for warfarin (INR 2-3) Connolly. N Engl J Med 2009.
29 DABIGATRAN RE-LY TRIAL Event Warfarin (% per yr) Dabigatran 110 mg (% per yr) Stroke or systemic embolism Stroke Hemorrhagic Ischemic * 1.11* Dabigatran 150 mg (% per yr) 1.01* 0.10* 0.92* Mortality Major bleed * 3.11 *statistically significant (p < 0.05) 64% Time-in range for warfarin (INR 2-3) Connolly. N Engl J Med 2009.
30 DABIGATRAN RE-LY TRIAL Event Warfarin (% per yr) Dabigatran 110 mg (% per yr) Stroke or systemic embolism Stroke Hemorrhagic Ischemic * 1.11* Dabigatran 150 mg (% per yr) 1.01* 0.10* 0.92* Mortality Major bleed * 3.11 *statistically significant (p < 0.05) 64% Time-in range for warfarin (INR 2-3) Connolly. N Engl J Med 2009.
31 DABIGATRAN RE-LY TRIAL Non-hemorrhagic Adverse Effects Dabigatran 150 mg BID (%) Warfarin (%) P-values Dyspepsia* <0.001 Dizziness NS Peripheral edema NS Fatigue NS Arthralgia NS Nasopharyngitis NS Diarrhea NS ALT/AST > 3x UNL NS ALT/AST > 3x UNL w/ bilirubin > 2x UNL NS * Leading to discontinuation of therapy in 21% of patients Connolly. N Engl J Med 2009.
32 DABIGATRAN RE-LY TRIAL Non-hemorrhagic Adverse Effects Dabigatran 150 mg BID (%) Warfarin (%) P-values Dyspepsia* <0.001 Dizziness NS Peripheral edema NS Fatigue NS Arthralgia NS Nasopharyngitis NS Diarrhea NS ALT/AST > 3x UNL NS ALT/AST > 3x UNL w/ bilirubin > 2x UNL NS * Leading to discontinuation of therapy in 21% of patients Connolly. N Engl J Med 2009.
33 DABIGATRAN RE-LY TRIAL Hemorrhagic Adverse Events Dabigatran 110mg (%/yr) Dabigatran 150mg (%/yr) Warfarin (%/yr) P-value Major Bleeding GI bleed , , <0.001 Minor Bleeding <0.001, Connolly. N Engl J Med 2009.
34 DABIGATRAN RE-LY TRIAL Hemorrhagic Adverse Events Dabigatran 110mg (%/yr) Dabigatran 150mg (%/yr) Warfarin (%/yr) P-value Major Bleeding GI bleed , , <0.001 Minor Bleeding <0.001, Connolly. N Engl J Med 2009.
35 DABIGATRAN RE-LY TRIAL Hemorrhagic Adverse Events Dabigatran 110mg (%/yr) Dabigatran 150mg (%/yr) Warfarin (%/yr) P-value Major Bleeding GI bleed , , <0.001 Minor Bleeding <0.001, Connolly. N Engl J Med 2009.
36 DABIGATRAN RE-LY TRIAL Conclusions: Dabigatran 110 mg BID associated with similar rates of stroke and systemic embolism compared to warfarin, with lower raters of major hemorrhage. Dabigatran 150 mg BID associated with lower rates of stroke and systemic embolism compared to warfarin but similar rates of major hemorrhage. GI bleed was higher compared to warfarin. Connolly. N Engl J Med 2009.
37 DABIGATRAN RE-LY TRIAL SUBSEQUENT SUBGROUP ANALYSES Analysis Results Cohort with prior history of stroke or TIA Warfarin naïve vs. warfarin experienced patients Subgroups undergoing cardioversion Study site-specific INR control Older vs. younger patients Consistent with RE-LY overall population No difference b/w dabigatran vs. warfarin No difference b/w dabigatran vs. warfarin Advantages of dabigatran (vs. warfarin) more pronounced at study sites with poor INR control < 75 yrs: bleed lower in dabigatran > 75 yrs: extracranial, GI and non-gi extracranial bleeding higher in dabigatran Lancet Neurol 2010., Circulation 2010., Circulation 2011., Circulation 2011., Lancet 2010.
40 CASE #1 A patient has recently diagnosed atrial fibrillation and is currently on dronadrerone therapy. The last CrCl of the patient was calculated at 25 ml/hr. Which of the following medications would be contraindicated for use of atrial fibrillation stroke prevention? A. Rivaroxaban B. Dabigatran C. Apixaban D. Warfarin
41 CASE # 2 A 71 year old male comes into your anticoagulation clinic asking to be switched from Xarelto due to high cost the cheaper alternative warfarin. He is using this medication for atrial fibrillation stroke prevention. What is the appropriate way to convert this patient? A. Initiate warfarin and continue Xarelto until INR within 2-3 B. Discontinue Xarelto and initiate warfarin in 48 hrs (due to Xarelto T 1/2 ) C. Initiate warfarin, discontinue Xarelto, and initiate enoxaparin 1 mg/kg SC BID until INR within 2-3 D. Initiate warfarin and discontinue Xarelto at the same time
42 RIVAROXABAN Brand Name: Xarelto 1 st oral direct factor Xa inhibitor approved in US MOA: reversibly binds to active site of coagulation factor Xa without antithrombin mediation Gonsalves. Mayo Clinic 2013.
43 RIVAROXABAN PK/PD Supplied: 10 mg, 15 mg, and 20 mg tablets Absorption: Bioavailibility is dose-dependent. 10 mg dose = % and not effected by food. 20 mg dose = 66%, increases with food to 76% 15 mg and 20 mg tablets recommended to take with food Drugs altering gastric ph do not effect bioavailability AUC and C max decrease by 29% and 56% respectively when administered distal to the stomach (ie. Small intestine via feeding tube) C max occurs 2-4 hrs after administration Xarelto. PI 2011.
44 RIVAROXABAN PK/PD Distribution: Plasma protein binding 92 95% Volume of distribution = 50L Metabolism: CYP3A4/5, CYP2J2, and hydrolysis to inactive metabolites Excretion: 33% unchanged in urine, rest in urine/feces as inactive metabolites DDI: CYP 3A4 inhibitors/inducers Xarelto. PI 2011.
45 RIVAROXABAN INDICATIONS FDA approved indications/dose: Non-valvular atrial fibrillation CrCl 50 ml/min: 20 mg daily, with evening meal CrCl ml/min: 15 mg daily, with evening meal *CrCl < 30 ml/min: excluded from ROCKET AF trial DVT/PE treatment 15 mg twice daily with food x 21 days, 20 mg daily with food DVT ppx following hip or knee replacement 10 mg daily Xarelto. PI 2011.
46 RIVAROXABAN BLACK BOX WARNING Discontinuing Xarelto places patients at an increased risk of thrombotic events. To reduce this risk, consider administering another anticoagulant if Xarelto must be discontinued for a reason other than pathological bleeding Epidural or spinal hematomas have occurred in patients treated with Xarelto who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis Xarelto. PI 2011.
47 RIVAROXABAN SWITCHING FROM XARELTO TO WARFARIN No clinical trial data available Xarelto affects INR, so INR measurements may not be accurate for determining appropriate dose of warfarin From warfarin to Xarelto From Xarelto to warfarin Between Xarelto and anticoagulants other than warfarin Discontinue warfarin, initiate Eliquis once INR is < 3.0 Discontinue Eliquis, begin both parenteral anticoagulant and warfarin at the time of the next Eliquis dose, discontinue parenteral once INR with goal range Discontinue one being taken and begin other at the next scheduled dose Xarelto. PI 2011.
48 RIVAROXABAN LITERATURE Indication VTE ppx in THA VTE ppx in TKA VTE treatment Stroke prevention in AF Trial RECORD I RECORD II RECORD III RECORD IV EINSTEIN DVT EINSTEIN EXT EINSTEIN PE ROCKET AF ACS ATLAS ACS 2 TIMI 51
49 RIVAROXABAN LITERATURE Indication VTE ppx in THA VTE ppx in TKA VTE treatment Stroke prevention in AF Trial RECORD I RECORD II RECORD III RECORD IV EINSTEIN DVT EINSTEIN EXT EINSTEIN PE ROCKET AF ACS ATLAS ACS 2 TIMI 51
50 RIVAROXABAN ROCKET AF TRIAL Atrial Fibrillation Randomized, double blind, double dummy N = 14,171 Inclusion: CHADS 2 2 -mean CHADS 2 = 3.1 -INR w/in target 55% of time Rivaroxaban 20 mg daily 15 mg for CrCl Warfarin INR target 2.5 ( inclusive) Exclusion: CrCl < 30 Monthly monitoring and adherence to standard of care guidelines Primary Endpoint: Stroke or non-cns systemic embolism Secondary Endpoints: composite of stroke, systemic embolism, or death from CV causes; MI; major and non-major bleeding events Patel. N Engl J Med 2011.
51 RIVAROXABAN ROCKET AF TRIAL Events: stroke or systemic embolism Rivaroxaban = 1.7 %/yr Warfarin = 2.2 %/yr P-value = < for noninferiority Patel. N Engl J Med 2011.
52 RIVAROXABAN ROCKET AF TRIAL Events: stroke or systemic embolism Rivaroxaban = 2.1%/yr Warfarin = 2.4 %/yr P-value = < for noninferiority Patel. N Engl J Med 2011.
53 RIVAROXABAN ROCKET AF TRIAL Patel. N Engl J Med 2011.
54 RIVAROXABAN ROCKET AF TRIAL Patel. N Engl J Med 2011.
55 RIVAROXABAN ROCKET AF TRIAL Patel. N Engl J Med 2011.
56 RIVAROXABAN ROCKET AF TRIAL Patel. N Engl J Med 2011.
57 RIVAROXABAN ROCKET AF TRIAL Conclusions: Rivaroxaban is noninferior to warfarin for the prevention of stroke or systemic embolism No significant difference in risk of major bleeding, however intracranial and fatal bleeding occurred less frequently in the rivaroxaban group
58 CASE # 2 A 71 year old male comes into your anticoagulation clinic asking to be switched from Xarelto due to high cost the cheaper alternative warfarin. He is using this medication for atrial fibrillation stroke prevention. What is the appropriate way to convert this patient? A. Initiate warfarin and continue Xarelto until INR within 2-3 B. Discontinue Xarelto and initiate warfarin in 48 hrs (due to Xarelto T 1/2 ) C. Initiate warfarin, discontinue Xarelto, and initiate enoxaparin 1 mg/kg SC BID until INR within 2-3 D. Initiate warfarin and discontinue Xarelto at the same time
59 CASE #3 A patient taking Eliquis 5 mg orally twice daily is to be started on fluconazole 400 mg daily for an extended period of time to treat a fungal infection. What is the appropriate action to take while fluconazole is being administered? A. Reduce the dose to 2.5 mg twice daily B. Reduce the dose to 5 mg once daily C. Discontinue Eliquis until the infection resolves D. Switch the patients anticoagulation to Xarelto
60 APIXABAN Brand Name: Eliquis Most recently FDA approved NOA in U.S. December 2012 MOA: selectively and reversibly inhibits free- and clot-bound factor Xa as well as prothrombinase activity Eliquis. PI 2011.
61 APIXABAN PK/PD Supplied: 2.5 mg and 5 mg tablets Absorption: Bioavailability = 50%, food does not affect Absorbed throughout entire GI tract, distal small bowel and ascending colon = 55% of absorption C max = 3 to 4 hrs after administration Distribution: Plasma protein binding = 87%, volume of distribution = 21 L Eliquis. PI 2011.
62 APIXABAN PK/PD Metabolism: Mainly via CYP3A4, minor CYP1A2, 2C9, 2C8, 2C19, 2J2 to inactive metabolites Elimination: Oral T 1/2 = 12 hrs Renal excretion accounts for 27% of total clearance DDI: Inhibitors/inducers of CYP3A4 and P-gp PI states Reduce dose to 2.5 mg or avoid use Eliquis. PI 2011.
63 APIXABAN INDICATIONS FDA approved Indication: Reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation Dose: 5 mg twice daily In patients with 2 of the following characteristics, 2.5 mg twice daily: *in ARISTOTLE trial Age 80 years ABW 60 kg SrCr 1.5 mg/dl Eliquis. PI 2011.
64 APIXABAN BLACK BOX WARNING Discontinuing Eliquis places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following discontinuation of Eliquis in clinical trials in patients with nonvalvular atrial fibrillation. If anticoagulation with Eliquis must be discontinued for a reason other than pathological bleeding, coverage with another anticoagulant should be strongly considered Eliquis. PI 2011.
65 APIXABAN CONVERTING FROM OR TO ELIQUIS No clinical trial data available Eliquis affects INR, so INR measurements may not be accurate for determining appropriate dose of warfarin From warfarin to Eliquis Discontinue warfarin, initiate Eliquis once INR is < 2.0 From Eliquis to warfarin Discontinue Eliquis, begin both parenteral anticoagulant and warfarin at the time of the next Eliquis dose, discontinue parenteral once INR with goal range Between Eliquis and anticoagulants other than warfarin Discontinue one being taken and begin other at the next scheduled dose Eliquis. PI 2011.
66 APIXABAN - LITERATURE Indication Trial VTE ppx in THA ADVANCE 3 VTE ppx in TKA ADVANCE 1 ADVANCE 2 Stroke prevention in AF ACS AVERROES ARISTOTLE APPRAISE
67 APIXABAN - LITERATURE Indication Trial VTE ppx in THA ADVANCE 3 VTE ppx in TKA ADVANCE 1 ADVANCE 2 Stroke prevention in AF ACS AVERROES ARISTOTLE APPRAISE
68 Inclusion: CHADS Mean CHADS 2 = 2.1 Exclusion: - SrCr >2.5 mg/dl or CrCL < 25 ml/min APIXABAN ARISTOTLE TRIAL Randomized, double blind, double dummy N = 18,201 *2.5 mg BID in pts with 2 of the following: - age 80 years - ABW 60 kg - SCr 1.5 mg/dl Apixaban 5 mg BID *2.5mg in select pts Warfarin (target INR 2-3) Primary outcomes: stroke or systemic embolism Granger. N Engl J Med 2011.
69 APIXABAN ARISTOTLE TRIAL Granger. N Engl J Med 2011.
70 APIXABAN ARISTOTLE TRIAL Granger. N Engl J Med 2011.
71 APIXABAN ARISTOTLE TRIAL Granger. N Engl J Med 2011.
72 APIXABAN ARISTOTLE TRIAL Conclusions: Apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality
73 CASE #3 A patient taking Eliquis 5 mg orally twice daily is to be started on fluconazole 400 mg daily for an extended period of time to treat a fungal infection. What is the appropriate action to take while fluconazole is being administered? A. Reduce the dose to 2.5 mg twice daily B. Reduce the dose to 5 mg once daily C. Discontinue Eliquis until the infection resolves D. Switch the patients anticoagulation to Xarelto
74 ATRIAL FIBRILLATION STROKE PREVETION SUMMARY Primary efficacy Stroke or Systemic Embolism: All agents non-inferior to warfarin Dabigatran and apixaban demonstrated superiority Rivaroxaban only demonstrated superiority in per-protocol analysis Hemorrhagic stroke: All agents significantly better than warfarin Ischemic stroke: Only dabigatran significantly better than warfarin Major bleed: Only apixaban significantly safer than warfarin No difference with dabigatran and rivaroxaban All cause mortality: Only apixaban significantly lower than warfarin All agents provide an approximate 10% reduction
75 CONCLUSIONS FOR NEW OA s Increased oral therapeutic options for patients that work independent of Vitamin K pathway Overcome some of warfarin's shortcomings: slow onset of action, variable pharmacologic effects, food-drug interactions, need for close monitoring Limited by high cost, lack of specific antidotes and long term safety data Until further data available, avoid new OA s in pregnancy, patients with mechanical heart valves, and severe renal insufficiency
Objectives Atrial Fibrillation and Prevention of Thrombotic Complications: Therapeutic Update Andrea C. Flores Pharm.D Pharmacy Resident at the Miami VA Healthcare System Review the epidemiology, pathophysiology
Devang M. Desai, MD, FACC, FSCAI Chief of Interventional Cardiology Director of Cardiac Catheterization Lab St. Mary s Hospital and Regional Medical Center A.Fib affects 2.2 million Americans. The lifetime
Analyzing Clinical Trial Findings of the Efficacy and Safety Profiles of Novel Anticoagulants for Stroke Prevention in Atrial Fibrillation Drew Baldwin, MD Virginia Mason Seattle, Washington NCVH May 29,
Breadth of indications matters One drug for multiple indications Sylvia Haas, MD, PhD Formerly of the Technical University of Munich Munich, Germany Disclosures: Sylvia Haas 1 Novel oral anticoagulants:
Objectives New and Emerging Anticoagulants Adraine Lyles, PharmD, BCPS Clinical Pharmacy Specialist VCU Medical Center Describe the pharmacology of the novel oral anticoagulants Discuss the clinical evidence
Kevin Saunders MD CCFP Rivergrove Medical Clinic Wellness Institute @ SOGH April 17 2013 Family physician with Rivergrove Medical Clinic Practice in the north end since 1985 Medical Director of the Wellness
Anticoagulation in the 21 st Century Adam Karpman, D.O. Saint Francis Medical Center/Oklahoma State University Medical Center Disclosures: None Atrial Fibrillation Most common arrhythmia in clinical practice.
Antiplatelet and Antithrombotic Therapy Dr Curry Grant Stroke Prevention Clinic Quinte Health Care Disclosure of Potential for Conflict of Interest Dr. F.C. Grant Atrial Fibrillation FINANCIAL DISCLOSURE:
STROKE PREVENTION IN ATRIAL FIBRILLATION OBJECTIVE: To guide clinicians in the selection of antithrombotic therapy for the secondary prevention of ischemic stroke and arterial thromboembolism in patients
FDA Approved Oral Anticoagulants Generic (Trade Name) Warfarin (Coumadin, Jantoven ) 1 FDA approved indication Prophylaxis and treatment of venous thromboembolism (VTE) Prophylaxis and treatment of thromboembolic
Anticoagulation: How Do I Pick From All the Choices? Jeffrey H. Neuhauser, DO, FACC BHHI Primary Care Symposium February 28, 2014 Atrial Fibrillation 2 Atrial Fibrillation The most common arrhythmia encountered
Update on New Anticoagulants (Apixaban, Dabigatran and Rivaroxaban) Patient Safety Daniel B. DiCola, MD and Paul Ament,, Pharm.D Excela Heath, Latrobe, PA Disclosures: Paul Ament discloses that he receives
Deniz Yavas, PharmD PGY-2 Ambulatory Care Pharmacy Resident Detroit Veterans Affairs Medical Center } Most common arrhythmia 0.4-1% of Americans (2.2 mil people) 1,2 } Incidence increases with age 6% (65
New Anticoagulants: Are we Ready to Replace Warfarin? Carole Goodine, RPh Horizon Health Network Stroke Conference 2011 Warfarin Decreases stroke risk by 60-70% Superior to ASA and ASA plus clopidogrel
Mary Bradbury, PharmD, BCPS Clinical Pharmacy Specialist, Cardiac Surgery September 18, 2012 Mary.firstname.lastname@example.org This presentation will discuss unlabeled and investigational use of products The author
Xarelto (Rivaroxaban) Hightly selective, reversible, direct oral FXa inhibitor Maxium concentratiion after 2 to 4 hrs High bioavailability(66%),increase with food ( suggest with food) 1/3 from renal excretion,
To Clot or Not What s New In Anticoagulation? Anita Ralstin, MS CNS CNP 1 Clotting Cascade 2 Anticoagulant drug targets Heparin XI VIII IX V X VII LMWH II Warfarin Fibrin clot 1 Who Needs Anticoagulation
Stroke Prevention in Atrial Fibrillation: New Oral Anti-Coagulants No More INRs Ashkan Babaie, MD Arrhythmia Service Providence Heart Clinic June 8 th, 2014 Goals Discuss the data behind approval of NOACs
Objectives Just for the RECORD: Rivaroxaban joins the US Anticoagulation Arsenal Anne P. Spencer, PharmD, FCCP, BCPS (AQ Cardiology) Cardiovascular Care Pharmacy Specialist Roper Saint Francis Healthcare
Disclosures The New Oral Anticoagulants: Are they better than Warfarin? Alan P. Agins, Ph.D. does not have any actual or potential conflicts of interest in relation to this CE activity. Alan Agins, Ph.D.
Management for Deep Vein Thrombosis and New Agents Mark Malesker, Pharm.D., FCCP, FCCP, FASHP, BCPS Professor of Pharmacy Practice and Medicine Creighton University 5 th Annual Creighton Cardiovascular
Oral Anticoagulants: What s New? Sallie Young, Pharm.D., BCPS (AQ-Cardiology) Clinical Pharmacy Specialist, Cardiology Penn State Hershey Medical Center email@example.com August 2012 Oral Anticoagulant
Anticoagulation Therapy Update JUDY R. WALLING, FNP-BC ARRHYTHMIA MANAGEMENT MUSC CARDIOLOGY Outline Who do we anticoagulate? Review classes of Anticoagulants Review examples of Anticoagulants Review CHADS2
Anticoagulation in Atrial Fibrillation Parag P. Patel, MD FACC Disclosures Eliquis Speakers Bureau 1 Clinical Scenario Ms. L is a 76F admitted to the stroke service with a dense right sided hemiparesis
New Oral Anticoagulants in the Management of Atrial Fibrillation June, 2012 By Deborah K Brokaw, Pharm.D. Introduction Since the 1950 s, the only orally available anticoagulant has been the vitamin K antagonist
New oral anticoagulants and antiplatelets: Where do they fit? Meredith Hollinger, PharmD BCPS Clinical Pharmacy Specialist, Cardiology September 2012 Objectives Describe the mechanisms of action for novel
Guideline for the Prescribing of Novel Oral Anticoagulants (NOACs): Dabigatran (Pradaxa ), Rivaroxaban (Xarelto ), Apixaban (Eliquis ) The contents of this CPG are to be used as a guide. Healthcare professionals
Page 1 WOMEN AT RISK Anticoagulation Issues In Atrial Fibrillation WOMEN AT RISK Anticoagulation Issues In Atrial Fibrillation J E A N N A P P I, P H A R M. D., F C C P, B C P S Accreditation: Pharmacists:
Anticoagulation For Atrial Fibrillation New Agents In A New Era Arjun V Gururaj, MD Arrhythmia and Electrophysiology Nevada Heart and Vascular Center Disclosures Biotronik Speaker Clinical investigator
This policy has been developed through review of medical literature, consideration of medical necessity, generally accepted medical practice standards, and approved by the IEHP Pharmacy and Therapeutics
Xarelto (Rivaroxaban): Effective in a broad spectrum Joep Hufman, MD Medical Scientific Liason Xarelto : Effective in a broad spectrum Introduction Therapeutic areas SPAF VTE Prevention VTE treatment Practical
Speaker Disclosure Matthew K. Pitlick, Pharm.D., BCPS St. Louis College of Pharmacy/VA St. Louis HCS firstname.lastname@example.org Matthew K. Pitlick, Pharm.D., BCPS declares no conflicts of interest, real or apparent,
New Oral Anticoagulants Tracy Minichiello, MD Associate Professor of Medicine Chief, San FranciscoVA Anticoagulation and Thrombosis Service Ansell, J. Hematology Copyright 2010 American Society of Hematology.
Key Points to consider when prescribing NOACs Introduction Three new/novel oral anticoagulants (NOAC) have been licensed in Ireland since 2008: Dabigatran Etexilate (Pradaxa ) 75mg, 110mg, 150mg. Rivaroxaban
Venous Thromboembolism: Long Term Anticoagulation Dan Johnson, Pharm.D. Disclosures No financial relationships with products discussed Off-label use of drug therapy always discussed Objectives Review clinical
ΠΟΙΟ ΑΝΤΙΠΗΚΤΙΚΟ ΓΙΑ ΤΟΝ ΑΣΘΕΝΗ ΜΟΥ? ΚΛΙΝΙΚΑ ΠΑΡΑΔΕΙΓΜΑΤΑ Σωκράτης Παστρωμάς Καρδιολόγος Νοσοκομείο Ερρίκος Ντυνάν The AF epidemic Mayo Clinic data (assuming a continued increase in the AF incidence) Mayo
New Treatments for Stroke Prevention in Atrial Fibrillation John C. Andrefsky, MD, FAHA NEOMED Internal Medicine Review course May 5 th, 2013 Classification Paroxysmal atrial fibrillation (AF) Last < 7
Carmarthen Cardiac Update Course AF, Stroke Risk and New Anticoagulants Dr Hamsaraj Shetty, B.Sc, FRCP (London & Edinburgh) Consultant Physician & Honorary Senior Lecturer University Hospital of Wales,Cardiff
Antiplatelet and Antithrombotics From clinical trials to guidelines Ashraf Reda, MD, FESC Prof and head of Cardiology Dep. Menofiya University Preisedent of EGYBAC Chairman of WGLVR One of the big stories
Novel Anticoagulation Agents DISCLOSURES James W. Haynes, MD Department of Family Medicine Univ of TN Health Science Center (Chattanooga) Objectives Understand mechanism of action behind the NOAC agents
Non- Valvular Atrial Fibrillation and Stroke Prevention: Which OAC Do I Choose Warfarin vs the NOACs Dr. Lori McIntosh D.O. Board Certified Neurologist Objectives Be able to list the current options of
Name: generic (trade) Rivaroxaban (Xarelto ) HERTFORDSHIRE MEDICINES MANAGEMENT COMMITTEE (HMMC) RIVAROXABAN RECOMMENDED see specific recommendations for licensed indications below What it is Indications
Stroke Prevention in Atrial Fibrillation: Commencing Non- Oral Anticoagulants in GP setting Dr Chuks Ajaero FMCP FRACP Cardiologist QEH, NALHN, SA Heart & Central Districts Disclosures NIL Classification
Dabigatran (Pradaxa) Guidelines Dabigatran is a new anticoagulant for reducing the risk of stroke in patients with atrial fibrillation. Dabigatran is a direct thrombin inhibitor, similar to warfarin, without
Long term anticoagulant therapy in patients with atrial fibrillation at high risk of stroke: a new scenario after RE-LY trial Camillo Autore Università di Roma Sapienza II Facoltà di Medicina e Chirurgia
The New Anticoagulants are Here! Do you know how to use them? Arrhythmia Winter School February 11 th, 2012 Jeff Healey RELY: A New Era in AF Connolly SJ et al. N Engl J Med 2009;361:1139-1151 ROCKET-AF:
New Antithrombotic Agents DISCLOSURE Relevant Financial Relationship(s) Speaker Bureau - None Consultant Amgen Tom DeLoughery, MD FACP FAWM Oregon Health and Sciences University What I am Talking About
TEGH Family Practice Clinic Day April 4, 03 Use of Anticoagulants in 03: What s New (and What Isn t) Bill Geerts, MD, FRCPC Director, Thromboembolism Program, Sunnybrook HSC Professor of Medicine, University
Page 1 of 9 ANALYTE NAME AND STRUCTURE - RIVAROXABAN SYNONYMS Xarelto CATEGORY Anticoagulant TEST CODE PURPOSE Therapeutic Drug Monitoring GENERAL RELEVANCY BACKGROUND Xarelto (rivaroxaban) is an orally
Winship Cancer Institute of Emory University New Anticoagulants: When and Why Should I Use Them? Christine L. Kempton, MD, MSc Associate Professor of Pediatrics and Hematology and Medical Oncology Hemophilia
~~Marshfield Labs Presents~~ Laboratory Monitoring of Anticoagulant Therapy Session 3 of 4 Michael J. Sanfelippo, M.S. Technical Director, Coagulation Services Session 3 Topics Direct Thrombin Inhibitors:
Comparative Anticoagulation Laurajo Ryan, PharmD, MSc, BCPS, CDE Clinical Associate Professor The University of Texas at Austin College of Pharmacy The University of Texas Health Science Center Pharmacotherapy
Medication Policy Manual Policy No: dru361 Topic: Pradaxa, dabigatran Date of Origin: September 12, 2014 Committee Approval Date: September 12, 2014 Next Review Date: September 2015 Effective Date: November
The New Kids on the Block: Oral Anticoagulants Lauren E. Odum, PharmD, BCPS Clinical Assistant Professor UMKC School of Pharmacy at MU April 11, 2014 Objectives Be able to Understand the major trials leading
Essentia Health Med Moment Short Video Tune-Up A brief overview of a new medication, or important new medication information Rivaroxaban (Xarelto ) by Richard Mullvain RPH BCPS (AQC) Current - August 2011
Novel OACs: How should we use them?" Iqwal Mangat, MD FRCPC" Director, Arrhythmia Service, St. Michaelʼs Hospital" Assistant Professor of Medicine, University of Toronto" Presenter Disclosure Dr. Iqwal
Cardiology Update 2014 Update on the Novel Oral Anticoagulants (NOACS) Raymond Kawasaki, MD AMG Cardiology December 6, 2014 Disclosures I have no disclosures relevant to this presentation Contents I. The
Novel Anticoagulants Kathleen Ozsvath, MD Associate Professor of Surgery, Albany Medical Center Partner, The Vascular Group, Albany, NY Chief of Vascular Services, Samaritan and St. Mary s Hospital, Troy,
NEWER ANTICOAGULANTS: FOCUS ON STROKE PREVENTION IN ATRIAL FIBRILLATION AND DEEP VEIN THROMBOSIS/PULMONARY EMBOLISM Carol Lee, Pharm.D., Jessica C. Song, M.A., Pharm.D. INTRODUCTION For many years, warfarin
ABOUT XARELTO CLINICAL STUDIES FAST FACTS Xarelto (rivaroxaban) is a novel, oral direct Factor Xa inhibitor. On September 30, 2008, the European Commission granted marketing approval for Xarelto for the
Optimizing Anticoagulation Selection for Your Patient C. Andrew Brian MD, FACC NCVH 2015 Who Needs to Be Anticoagulated and What is the Patient s Risk? 1. Atrial Fibrillation ( nonvalvular ) 2. What regimen
New Oral Anticoagulants Rebecca Hanratty, MD Denver Health April 12, 2011 Overview Why we need alternatives to warfarin Review of the 3 new oral anticoagulants Results from major trials: Thromboprophylaxis
Experience matters: Practical management in your hospital Dr AGG Turpie McMaster University, Hamilton, ON, Canada Disclosures AGG Turpie has acted as a consultant for Bayer HealthCare, Janssen, Sanofi-Aventis,
2011 MFMER slide-1 Anticoagulation Management Insanity: doing the same thing over and over again and expecting different results Fadi Elias Shamoun, MD Mayo Clinic in Arizona Albert Einstein Anticoagulation
Novel Anticoagulants in the Elderly Bahar Matusik, PharmD, BCPS Assistant Professor Department of Pharmacy Practice & Administration University of Saint Joseph, School of Pharmacy Disclosures Dr. Bahar
Update on atrial fibrillation Prevention of thrombo - embolic complications Felicita Andreotti Dept of Cardiovascular Science Catholic University, Rome, IT Consultant or speaker in past 2 years for Amgen,
Indication Agent Standard Dose Comments and Dose Adjustments VTE Prophylaxis All Services UFH 5,000 units SC q 8 h See EMR adult VTE prophylaxis CI order set Enoxaparin See service specific dosing Assess
SEPTEMBER 2012 CCPN SPAF Tool STROKE PREVENTION IN ATRIAL FIBRILLATION (SPAF): POCKET REFERENCE Approximately 20% of all strokes are attributable to Atrial Fibrillation (AF). 1 Of these, 20% will result
MEDICAL ASSISTANCE HBOOK PRI AUTHIZATION OF PHARMACEUTICAL SERVICES I. Requirements for Prior Authorization of Anticoagulants A. Prescriptions That Require Prior Authorization Prescriptions for Anticoagulants
Update on Antiplatelets and anticoagulants Timir Paul, MD, PhD Antiplatelets Indications Doses Long term use (beyond 12 months) ASA and combination use of NSAIDS ASA resistance Plavix resistance Plavix
Optimizing Anticoagulation Therapy for Older Adults with Atrial Fibrillation: The New Oral Agents" None Disclosures Brad Hein, PharmD Associate Professor of Pharmacy The University of Cincinnati Winkle
Bios 6648: Design & conduct of clinical research Section 1 - Specifying the study setting and objectives 1. Specifying the study setting and objectives 1.0 Background Where will we end up?: (a) The treatment
Reversing the New Anticoagulants Disclosure Susan C. Lambe, MD Assistant Clinical Professor Department of Emergency Medicine University of California, San Francisco Roadmap for today 1 Roadmap for today
New Oral Anticoagulant Drugs What monitoring if any is required? Michelle Williamson Supervising Scientist High Throughput Haematology Pathology Queensland PAH Laboratory Overview Background What new oral
MEDICAL ASSISTANCE HBOOK I. Requirements for Prior Authorization of Anticoagulants A. Prescriptions That Require Prior Authorization Prescriptions for Anticoagulants which meet any of the following conditions
New Oral Anticoagulants How safe are they outside the trials? Objectives The need for anticoagulant therapy Indications for anticoagulation Traditional anticoagulant therapies Properties of new oral anticoagulants
Rivaroxaban A new oral anti-thrombotic Dr. Hisham Aboul-Enein Professor of Cardiology Benha University 12/1/2012 Agenda Ideal anticoagulant. Drawbacks of warfarin. Rivaroxaban in clinical trails. Present
Version 3 August 2014 NHS DORSET CLINICAL COMMISSIONING GROUP POSITION STATEMENT ON ORAL ANTICOAGULANTS IN ATRIAL FIBRILLATION Dorset CCG commissions the use of newer oral anti-coagulants in accordance