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TSOACs:
Target Specific Oral Anticoagulants
Glee Lenoir, Pharm D.
Pharmacy Clinical Coordinator The Medical Center
Nursing Conference March 2015
Disclosures
I have served as an advisory board member, consultant, speaker, and / or received research funding from:
Sanofi-Aventis Janssen Pharmaceuticals
Off-label use may be mentioned: dabigatran, rivaroxaban, apixaban, edoxaban, FEIBA, Kcentra
Anticoagulant Therapy
What are the options ?
1930s – heparin1950s – warfarin
1990s – Low molecular weight heparin
1990s – direct thrombin inhibitors
2000s – factor Xa inhibitor
2010s – TSOACs
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Warfarin (Coumadin
®)
Dosing Roulette Oral Gold Standard
“Rat Poison?”
Warfarin (Coumadin
®)
• Action: inhibits vitamin K dependent clotting factors
• factors VII, IX, X, II
• Half Life: 20-60 hours (avg:40hrs)
• “it takes 10-14 days to reach steady-state” • Monitoring: PT/INR
• Home monitoring finger stick devices
• Dosing: dependent on INR
• INR Goal: 2-3 usual (2.5-3.5 other) • Cost- generic $4/month
Warfarin (Coumadin
®)
• Indications: Prophylaxis and treatment for VTE and thromboembolic disorders, adjunct to reduce risk of systemic embolism such as recurrent MI or stroke • Antidote: Vitamin K (phytonadione)
• Available as oral tablets
• Subcutaneous route is preferred injection route • IM route should be avoided due to risk of hematoma
formation
• May be given IV for life-threatening bleeding
• Administer IV slowly not to exceed 1mg/min • Dilute 10mg dose in 50ml saline over 20 min • Does not work immediately!
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Warfarin (Coumadin
®)
Food/nutrient interactions
Examples: • Foods high in vitamin K
• Dark green leafy vegetables • Nutritional supplements
• Ensure, Boost, Slim Fast, Carnation instant breakfast • Vitamins, minerals, herbals • Alcohol (Et2OH)
• Acute ingestion- increase INR • Chronic ingestion- decrease INR • EtOH-related liver disease-
increase INR • Independently increases
hemorrhagic risk
Partial List of Anticoagulant Drugs Under Development
Weitz JI et al. Chest 2012
Target Specific Oral Anticoagulants
Dabigatran – Pradaxa(Boehringer Ingelheim)
Rivaroxaban – Xarelto
(Janssen)
Apixaban – Eliquis
(Bristol-Myers Squibb / Pfizer) Edoxaban– Savaysa
(Daiichi Sankyo)
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Target Specific Oral Anticoagulants
Approval History
Dabigatran Rivaroxaban Apixaban
VTE prophylaxis (THR, TKR) Europe – Mar 2008 Canada – Jun 2008 Europe – Sep 2008 Canada – Sep 2008 USA – July 2011 Europe – May 2011 Canada – Mar 2012 USA –Mar 2014 Non-Valvular Afib (NVAF) Canada – Oct 2010 USA – Oct 2010 Europe – Aug 2011 USA – Nov 2011 Europe – Dec 2011 Canada – Jan 2012 Europe – Nov 2012 Canada – Dec 2012 USA – Dec 2012 VTE treatment Canada – Sep 2014
USA – Apr 2014 Europe – Jun 2014 Europe – Dec 2011 Canada – Feb 2012 USA – Nov 2012 Europe – Jul 2014 Canada – Sep 2014 USA – Aug 2014
Edoxaban was approved Jan 2015 in US for NVAF and VTE treatment; Canada -Nov 2013 for NVAF
Summary of Major Clinical Trials
Dabigatran Rivaroxaban Apixaban
VTE
prophylaxis VTE treatment NVAF
REMODEL REMOBILIZE RENOVATE RENOVATE 2 RECOVER REMEDY RESONATE RECOVER 2 RELY RELYABLE RECORD 1 RECORD 2 RECORD 3 RECORD 4 EINSTEIN-DVT EINSTEIN-EXT EINSTEIN-PE ROCKET-AF ADVANCE 1 ADVANCE 2 ADVANCE 3 AMPLIFY AMPLIFY-EXT ARISTOTLE AVERROES STARS J4 & J5 STARS J5
Hokusai VTE ENGAGE AF
Edoxaban
FDA Approved Indications
As of February, 2015
Dabigatran Rivaroxaban Apixaban Edoxaban VTE prophylaxis (THR, TKR)
x
x
Non-valvular Afib
VTE treatment
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Pharmacokinetics
* Despite short half-life, once daily dosing possible due to persistence of anti-Xa activity Harder S, Graff J. Eur J Clin Pharmacol 2013; 69(9):1617-33 Dabigatran Rivaroxaban Apixaban Edoxaban Target Thrombin Factor Xa Factor Xa Factor Xa
Peak Effect (h) 2 – 3 2 – 4 3 – 4 1-2 Half-life (h) 12 – 17 (14-17 elderly) (28 severe renal) 5 – 9 (11-13 elderly) ~12 10-14 Dosing Frequency
Twice daily Daily* Twice daily Daily
Clearance 80% Renal 20% Biliary 66% Renal 34% Biliary 25% Renal 75% Biliary 50%Renal 50%Biliary
Renal Dosing
Dabigatran
•
Non-valvular Afib : >50 ml/min 150mg po BID30-50 ml/min (+dronedarone or ketoconazole) 75mg po BID 15-30 ml/min 75mg po BID
<15 ml/min no recommendations
•
VTE treatment:>30 ml/min 150mg po BID (after 5-10 days of parenteral anticoagulation)
(if crcl<50 ml/min and is receiving P-gp inhibitor, then avoid coadministration)
<30 ml/min no recommendations
Hemodialysis: no recommendations Note hemodialysis removes ~57% over 4 hours
Renal Dosing
Rivaroxaban
•
Postoperative thromboprophylaxis (TKR,THR):>30 ml/min 10mg po daily <30 ml/min not recommended
•
Non-valvular Afib:>50 ml/min 20mg po daily 15-50 ml/min 15mg po daily <15 ml/min not recommended
•
VTE treatment:>30 ml/min 15mg po BID x 21 days, then 20mg po daily <30 ml/min not recommended
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Renal Dosing
Apixaban
•
Postoperative thromboprophylaxis (TKR,THR)2.5mg po BID beginning 12-24hrs post-op
(note: patients with “significant”, “impaired”, CrCl<30 ml/min were excluded from clinical trials)
•
Non-valvular Afib:5mg po BID unless two of the following exist: creatinine >1.5mg/dl; age >80 years; weight <60 kg then 2.5mg po BID
•
VTE treatment:10mg po BID x 7 days, then 5mg po BID
(note: patients with Cr>2.5 or CrCl<25 ml/min were excluded from clinical trials)
NVAF indication: ESRD requiring hemodialysis 5mg po BID; reduce to 2.5mg BID if age>80 yrs or weight <60 kg
Renal Dosing
Edoxaban
•
Non-valvular Afib:>95 ml/min DO NOT USE 50-95 ml/min 60mg po daily 15-50 ml/min 30mg po daily <15 ml/min no information
•
VTE treatment:>50 ml/min 60mg po daily (following 5-10days of parenteral anticoagulant)
15-50ml/min or <60kg or concomitant P-gp inhibitor 30mg po daily
Hemodialysis: does not significantly contribute to clearance
Drug Interactions
•
Dabigatran and edoxaban interact with drugs that affect the transporter P-glycoprotein (P-gp)•
Rivaroxaban and apixaban also interact withP-gp drugs, as well as those that affect the microsomal enzyme CYP3A4
•
Examples•
Increased risk of major bleeding seen in studies of all 3 drugs when used with anti-platelet agentsSchulman S, Crowther MA. Blood 2012; 119(13):3016-23 Harder S, Graff J. Eur J Clin Pharmacol 2013; 69(9):1617-33 Ketoconazole Rifampicin Cyclosporine
Itraconazole Clarithromycin Tacrolimus
Amiodarone Protease inhibitors Carbamazepine
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Laboratory Monitoring
Baumann-Kreuziger LM, et al. J Trauma Acute Care Surg 2012
Dabigatran Rivaroxaban Apixaban
PT / INR Increases with dose
Very insensitive
PT / INR and aPTT are both prolonged, but to a varying degree, and depend upon the
reagents used
aPTT Increases with dose Not linear, plateaus
Thrombin Time Most sensitive Normal TT = no drug Too sensitive No effect No effect
Other Ecarin clotting time
is the best assay, but is not widely
available
Anti-Xa assay can be used, but must be standardized to
the drug
Anti-Xa assay very similar to LMWH, and may not need to
re-calibrate?
Summary of Clinical Trials
Non-valvular Atrial fibrillation
VTE Prophylaxis
VTE Treatment
Summary of Clinical Trials
Non-valvular Atrial fibrillation
RE-LY
(Connolly SJ et al. NEJM 2009; 361:1139-51)•
N = 18,113 (mean CHADS2=2.1)•
Dabigatran 150 mg bid vs. warfarin•
Superior in efficacy when warfarin avg TTR 64%•
Similar rates of major bleeding•
Dabigatran associated with less ICH•
Significantly more GI bleeding•
MUST TAKE WITH FOOD!8
ROCKET AF
(Patel MR et al. NEJM 2011; 365:883-91)•
N = 14,264 (mean CHADS2=3.5)•
Rivaroxaban 20 mg daily vs. warfarin•
Rivaroxaban was non-inferior to warfarin•
No overall difference in major bleeding•
Rivaroxaban associated with less ICH andfatal bleeding, but more GI bleeding
•
Take with evening mealSummary of Clinical Trials
Non-valvular Atrial fibrillation
Summary of Clinical Trials
Non-valvular Atrial fibrillation
ARISTOTLE
(Granger CB et al. NEJM 2011; 365:981-92)•
N = 18,201 (mean CHADS2=2.1)•
Apixaban 5 mg bid vs. warfarin•
Apixaban was superior in preventing stroke with less overall bleeding and lower all cause mortality•
Apixaban associated with less ICH•
No increase in GI bleedingSummary of Clinical Trials
Non-valvular Atrial fibrillation
ENGAGE
AF-TIMI 48
(Giugliano RP NEJM 2013; 369:2093-2104)
•
N = 21,105 (mean CHADS2=2.8+1)•
Edoxaban 60 mg daily vs. warfarin•
Edoxaban was non-inferior in preventing stroke•
Edoxaban was associated with less ICH•
More GI bleeds9
Summary of Clinical Trials
VTE Prophylaxis (THR, TKR)
Rivaroxaban Apixaban vs.
Enoxaparin
•
Equal or better efficacy•
Similar bleeding risk•
Advantage of oral administrationBoth agents have been trialed for VTE prophylaxis in medically ill patients and were associated with unacceptable rates of bleeding
Summary of Clinical Trials
VTE Treatment
Dabigatran Rivaroxaban Apixaban vs. Conventional therapy•
Non-inferior to warfarin, with same or less overall bleeding risk•
Less major bleeding (eg. ICH)•
Edoxaban & dabigatran require 5-10 daysof overlap with parenteral anticoagulant
RE-MEDY = 65% EINSTEIN = 58% EINSTEIN-PE = 63%
AMPLIFY = 61% Hokusai VTE=65.6% Time in Therapeutic Range (INR 2.0 – 3.0)
Edoxaban
Management of Bleeding
* Activated charcoal indicated within 2 – 3 hours of drug ingestion ** Dabigatran has a very large volume of distribution (60 – 70 L); expect multiple dialysis sessions to be required
Dabigatran Rivaroxaban Apixaban
Antidote None None None
Activated charcoal*
Yes Yes Yes
Dialysis ~35% protein bound ~60% removed in 2 -3 h ** Highly protein bound Dialysis ineffective Highly protein bound Dialysis ineffective
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Hemostatic Agent Options for
Management of Bleeding
(None are approved in the US for this indication)
Name Category Available in US?
Aminocaproic acid antifibrinolytic Yes
Tranexamic acid antifibrinolytic Yes
Profilnine, Bebulin 3 factor PCC Yes
Cofact, Kanokad 4 factor PCC No
Octaplex, Kaskadil 4 factor PCC, + PC, PS No
Beriplex / Kcentra 4 factor PCC, + PC, PS Yes
FEIBA Activated PCC Yes
NovoSeven rfVIIa Yes
Use of Factor Concentrates for
Management of Bleeding
•
Factor Concentrates are NOT antidotes–
They create hypercoagulability–
Specific reversal agents are in trials•
Thrombotic risk is significant!•
Hospitals have in house protocols but there are no specific guidelines available•
Should be restricted forLIFE THREATENING
bleeding only!
Antidotes in development: Aripazine (PER977), Andexanet (PRT064445), Idarucizumab (BI 655075)
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Perioperative Management
•Lab testing – If TT (dabigatran) or anti-Xa (rivaroxaban, apixaban) are normal, drug has cleared. If tests are abnormal there is still drug on board but cannot quantitate risk
Drug Package Insert Recommendations Dabigatran For CrCl >50, stop 1 to 2 days prior
For CrCl <50, stop 3 to 5 days prior Consider longer* if major surgery, spinal
puncture, spinal or epidural catheter
Rivaroxaban Stop at least* 24 hours prior
Edoxaban
Apixaban Stop at least* 48 hours prior (moderate or high risk procedures)
Stop at least* 24 hours prior (low risk procedures)
*Clinical decisions should be individualized based on patient parameters that could influence clearance and risk of bleeding versus risk of clotting
Advantages
Disadvantages
•
Direct anticoagulants•
Predictable pharmacokinetics•
No bridging needed*•
No monitoring needed•
Few diet / drug interactions•
Renal / hepatic excretion•
No antidotes•
Unable to monitor directly•
Limited experience•
Lack of long-term safety dataTarget Specific Oral Anticoagulants
*most indications
Target Specific Oral Anticoagulants
To use or not to use ?
Non-valvular Atrial Fibrillation
•
Those already on warfarin, with good INR control, have little to gain by switching•
New agents may have better safety profile (less intracranial hemorrhage)•
Consider patient compliance and cost of drug and testing•
Drug interactions with the new agents and drugs for afib, etc. must be considered12
Target Specific Oral Anticoagulants
To use or not to use ?
Prevention of VTE
•
Dabigatran and edoxaban are not approved in the US for this indication•
Rivaroxaban and apixaban are good alternatives to LMWH / warfarin in this setting•
Look closely at the trial comparator dose of enoxaparin before chosing agent•
Approval currently only for THR and TKRTarget Specific Oral Anticoagulants
To use or not to use ?
Treatment of VTE
•
Special attention should be given to dosing regimens when prescribing/counseling•
Patients may no longer require hospitalization but should have careful follow-up•
Rivaroxaban and apixaban are also indicated for extended treatment of VTE after at least 6 months of treatment but more bleeding than placebo•
Malignancy•
Pregnancy•
Mechanical heart valves•
Thrombophilia (APC, PC, PS, AT double heterozygotes or homozygotes for FVL/PGM)•
Extremes of body weight•
Those with more than “low” bleeding risk•
Real world compliance (not on studies)Target Specific Oral Anticoagulants
To use or not to use ?
We need more experience in patients with:
RE-ALIGN Study
(NEJM 2013; 369:1206-14)
•Dabigatran vs. warfarin •Aortic and mitral valves •Terminated early due to
EXCESS thromboembolic and bleeding events in dabigatran group
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Take Home Points
The new oral anticoagulants are not necessarily better than warfarin; they are different, and each has advantages and disadvantages
Careful patient selection is crucial for the safe use of TSOACs
Management of bleeding complications
from the TSOACs is a major clinical challenge; we have no guidelines and “real world” clinical experience is limited
