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Answering the Call: The Role of Health-System Pharmacists to Improve Use of
Target-Specific Oral Anticoagulants
© 2014 Paradigm Medical Communications, LLC, except where noted. All rights reserved.
1
Faculty
Sarah A. Spinler, PharmD, FCCP,
FCPP, FAHA, FASHP, AACC, BCPS
AQ–Cardiology (Chair)
Professor of Clinical Pharmacy
Philadelphia College of Pharmacy
University of the Sciences
Philadelphia, PA
John Fanikos, RPh, MBA
Director of Pharmacy, Business
Brigham and Women’s Hospital
Boston, MA
Denise H. Rhoney, PharmD, FCCP,
FCCM, FNCS
Ron and Nancy McFarlane
Distinguished Professor and Chair
Division of Practice Advancement
and Clinical Education
UNC Eshelman School of Pharmacy
Chapel Hill, NC
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
Target-Specific Oral Anticoagulants
© 2014 Paradigm Medical Communications, LLC, except where noted. All rights reserved.
2
Agenda
• Welcome and Opportunities for Clinical Pharmacy Action
• Balancing Act: Risk Assessment in Anticoagulation Management
• Clinical Pharmacology of TSOAs: What's Important to Know
• Oral Anticoagulation use in Stroke Prevention in Atrial Fibrillation
• Oral Anticoagulation use in Deep Vein Thrombosis and Pulmonary Embolism
• Addressing Clinical Challenges: Focus on Coagulation Monitoring and Management of Bleeding
• Clinical Pharmacy Call to Action: Ensuring Appropriate Anticoagulation
• Panel Discussion/Interactive Case Review
Welcome and Opportunities for Clinical Pharmacy Action
Sarah Spinler, PharmD, FCCP, FCPP, FAHA, FASHP, AACC,BCPS–AQ Cardiology
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
Target-Specific Oral Anticoagulants
© 2014 Paradigm Medical Communications, LLC, except where noted. All rights reserved.
3
The Impact of Atrial Fibrillation
• AF will affect ≈6 million
Americans by 20501
• >70% is NVAF
• Leads to 100,000–125,000
embolic strokes/y2
• AF related stroke leads to2:
• Chronic disability
• Bedridden patients
• Constant nursing care
• >20% are fatal
1. Ciervo CA et al. J Am Osteopath Assoc. 2012;112:eS2-eS8. 2. Reiffel JA. Am J Med. 2014;127:e15-e16.
Republished with Permission of Am Osteopathic Assoc, from Ciervo CA et al, Stroke prevention in patients with atrial fibrillation: disease burden and
unmet medical needs, J Am Osteopath Assoc, 2012;112(9 Suppl 2):eS2-eS8; permission conveyed through Copyright Clearance Center.
AF, atrial fibrillation; NVAF, nonvalvular atrial fibrillation
The Impact of Venous Thromboembolism
• > 1 million pts worldwide have unprovoked VTE each year1
• VTE affects up to 900,000 people/y in US1,2
• 1/2 will have long-term complications
• Up to 1/3 will die within 1 mo of diagnosis
• Up to 1/3 will have a recurrence within 10 y
• PE • Leading preventable cause of death in hospitalized patients3
• Sudden death is 1st symptom in 1/4 of patients1
• Mortality rate without treatment ≈30%4
(vs 8% with adequate treatment )
1. Simes J et al. Circulation. 2014;130:1062-1071. 2. Raskob GE et al. Am J Prev Med. 2010;38(4 Suppl):S502-S509. 3. Walter RJ et al. Curr Med
Res Opin. 2014;30(10):1975-1989. 4. Carson JL et al. N Engl J Med 1992;326(19):1240-1245.
MI, myocardial infarction; PE, pulmonary embolism; VTE, venous thromboembolism
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
Target-Specific Oral Anticoagulants
© 2014 Paradigm Medical Communications, LLC, except where noted. All rights reserved.
4
Opportunities to Achieve Appropriate Anticoagulation
• 57% of patients with NVAF at high risk for stroke receive guideline-recommended anticoagulation1
• 1/3 of AF patients are not on anticoagulation but only 12% have contraindications2
• TTR on VKAs increases from 30%-60% with usual care to up to 60%–90% with anticoagulation management3
• ≈40% of patients taking OACs + aspirin had no documented indication for aspirin4
• Less than half of those with unprovoked VTE remain on long-term anticoagulation5
1. Jacobovitz S. J Am Coll Cardiol. 2014;64:226-228. 2. ACCEL: Probing the ORBIT-AF Registry. www.cardiosource.org/en/News-
Media/Publications/CardioSource-World-News/2013/October/ACCEL-Probing-the-ORBIT-AF-Registry.aspx/ . Accessed July 3, 2014. 3. Ansell JA.
http://excellence.acforum.org/sites/default/files/Patient%20Self%20Testing%20Presentation.pdf. Accessed July 14, 2014. 4. Steinberg BA et al; for the
ORBIT-AF Investigators and Patients. Circulation. 2013;128:721-728. 5. Simes J et al. Circulation. 2014;130:1062-1071.
ORBIT AF, Outcomes Registry for Better Informed Treatment of Atrial Fibrillation; OAC, oral anticoagulant; TTR, time in
therapeutic range; VKAs, vitamin K antagonists
There are clear opportunities for clinical pharmacists to take
an active role to improve anticoagulation management!
Balancing Act: Risk Assessment in Anticoagulation Management
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
Target-Specific Oral Anticoagulants
© 2014 Paradigm Medical Communications, LLC, except where noted. All rights reserved.
5
BleedingThrombosis
An ideal anticoagulant will provide the greatest reduction
in thromboembolism with the lowest incidence of bleeding.
1. Camm JA et al. Eur Heart J. 2012;33:2719-2747. 2. Ansell J et al. Chest. 2001;119:22S-38S. 3. Fuster V et al. J Am Coll Cardiol. 2001;38:1231-1266.
• Assess bleeding risk1,2
• Identify “red flags”2
• Control modifiable
risk factors2
• Select appropriate
anticoagulant2,3
• Dosage adjustment2,3
• Monitoring/adherence3
• Drug-drug interactions3
• Assess stroke risk1
• Control modifiable
risk factors2
• Evidence-based
anticoagulant regimen2,3
• Monitoring/adherence
• Drug-drug interactions2,3
Optimize Benefits, Minimize Risk
Goal of Anticoagulation Therapy
Risk Factor Score
C Congestive heart failure/LVEF ≤40% /1
H Hypertension /1
A2 Age ≥75 /2
D Diabetes mellitus /1
S2 Previous history of stroke, TIA, TE /2
V
Vascular disease, including prior MI,
peripheral artery disease, aortic
plaque
/1
A Age 65–74 /1
Sc Sex category = female /1
Total score /9
Risk Factor Score
H Hypertension* /1
AAbnormal renal or liver function
(1 point each)/2
S Previous history of stroke /1
BBleeding history or disposition
(anemia)/1
L Labile INRs /1
E Elderly: age >65 /1
DDrugs (antiplatelets or NSAIDs) or
alcohol (1 point each)/2
Total score /9
Assess Stroke Risk: CHA2DS2-VASc1,2 Assess Bleed Risk: HAS-BLED1,3
*Hypertension refers to uncontrolled hypertension
LVEF, left ventricular ejection fraction; TIA, transient ischemic attack; TE, thromboembolic event
Clinical Decision Aid: SPAF
1. Lahaye S et al. Thromb Haemost. 2014;111(3):465-473; online Suppl 2: 111.4. 2. Lip GYH, et al. Chest. 2010; 137: 263-272.3. Pisters R et al. Chest.
2010; 138: 1093-1100. Reproduced with permission from the American College of Chest Physicians.
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
Target-Specific Oral Anticoagulants
© 2014 Paradigm Medical Communications, LLC, except where noted. All rights reserved.
6
American College of Cardiology AnticoagEvaluator App for AF
Easy, fast way to assess stroke and bleeding risk and benefits vs risks of antithrombotic therapy
• Combination risk calculator uses CHADS2, CHA2DS2-VASc, HAS-BLED
• Enter patient characteristics at POC; get individualized annual risk of ischemic stroke, thromboembolism with concurrent annual risk of major bleed
• Compare antithrombotic therapy options based on clinical trials (ACTIVE-A, RE-LY, ROCKET-AF, ARISTOTLE)
Available at: https://itunes.apple.com/us/app/anticoagevaluator/id609795286?mt=8. Accessed 11/17/14. Available at:
https://play.google.com/store/apps/details?id=org.acc.AnticoagEvaluator&hl=en. Accessed 11/17/14.
POC, point of care
• Goal: Determine best anticoagulation strategy for individual
patient
• Stroke risk assessment using CHA2DS2-VASc• Most patients with CHA2DS2-VASc score >1 will derive net benefit from
well-managed anticoagulation, irrespective of bleeding risk score
• Patients with low CHA2DS2-VASc score and/or very high bleeding risk
may not be candidates for antithrombotic therapy (cases will be rare)
• Bleeding risk assessment: Performed only to identify
modifiable risk factors for bleeding
• HAS-BLED score NOT recommended (low C-statistic)
• Shared decision making: risk factors, cost, tolerability, patient preference, drug interaction potential, TTR if warfarin
AHA/ACC/HRS Recommendations for Objective Risk Assessment
AHA, American Heart Association; ACC, American College of Cardiology; HRS, Heart Rhythm Society; TTR, time to
response
January CT et al. J Am Coll Cardiol. 2014 Mar 28. pii: S0735-1097(14)01740-9.
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
Target-Specific Oral Anticoagulants
© 2014 Paradigm Medical Communications, LLC, except where noted. All rights reserved.
7
Risk Factors Risk Measure 95% CI
Patient Features
- Age (per decade increase)
- Male sex
HR = 1.17
HR = 1.56
1.11 – 1.24
1.22 – 2.00
Index Event
- PE
- Isolated distal DVT
HR = 1.19
HR = 0.49
0.87 – 1.63
0.34 – 0.71
Risk Factors
- Surgery
- Trauma-associated VTE*
HR = 0.36
HR = 0.51
0.21 – 0.62
0.32 – 0.87
Residual DVT
- Overall population
- Unprovoked VTE
OR = 1.50
OR = 1.24
1.11 – 2.03
0.90 – 1.71
Increased D-dimer OR = 2.36 1.65 – 3.36
*Compared with unprovoked VTE
Risk Factors for Recurrent VTE with Relative Strength of Association
Agnelli G et al. American Society of Hematology Education Book. 2013;1:471-477. Republished with permission of American Society of Hematology;
permission conveyed through Copyright Clearance Center, Inc.
CI, confidence interval; DVT, deep venous thrombosis; VTE, venous thromboembolism; OR, odds ratio; HR, hazard
ratio; PE, pulmonary embolism
Key Points
• Understand the personal and fiscal impact of stroke and DVT/VTE/PE
• Balanced risk assessment is important to• Identify patients at risk
• Help in treatment selection and planning
• In NVAF• CHA2DS2-VASc is recommended
• Bleeding risk assessment to identify modifiable risk factors
• In VTE• Few available tools
• Evaluate risk factors for recurrent VTE and consider bleeding risks
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
Target-Specific Oral Anticoagulants
© 2014 Paradigm Medical Communications, LLC, except where noted. All rights reserved.
8
Clinical Pharmacology: What’s Important to Know
Denise Rhoney, PharmD, FCCP,FCCM, FNCS
Dabigatran1 Rivaroxaban2 Apixaban3 Edoxaban4-8
Drug classDirect factor IIa
inhibitorDirect factor Xa inhibitor
Direct factor Xa
inhibitor
Direct factor Xa
inhibitor
Time to Cmax 1 h 2-4 h 3-4 h 1-2 h
CYP metabolism None
CYP3A4/5, CYP2J2, and
hydrolysis are the major
means of
biotransformation
Mainly by
CYP3A4
62% fecal
elimination
Renal excretion80% of absorbed
dose
66% of total dose; 36% as
unchanged drug27% 35% of total dose
Protein binding 35% 92%-95% 87% 40%–59%
Half-life 12-17 h 5-9 h ≈12 h
6–11 h4,5
9–11 h6
10–14 h8
Dosing frequency
NVAFBID QDay BID QDay
1. Pradaxa (dabigatran etexilate mesylate) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc.; 9/2014.
2. Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 9/2014. 3. Eliquis (apixaban) [prescribing information].
Princeton, NJ: Bristol-Myers Squibb Company; 8/2014. 4. Camm AJ et al. Drugs. 2011;71:1503-1526. 5. Ogata K et al. J Clin Pharmacol. 2010;50:743-
753. 6. Eikelboom JW et al. Circulation. 2010;121:1523-1532. 7. Bathala M et al. Drug Metab Dispos. 2012;40:2250-2255. 8. Bounameaux H et al.
Drugs. 2014;74:1209-1231.
TSOAs: Pharmacology
Cmax, time to maximum concentration; PK/PD, pharmacokinetics/pharmacodynamics
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
Target-Specific Oral Anticoagulants
© 2014 Paradigm Medical Communications, LLC, except where noted. All rights reserved.
9
TSOAs: Dosing
Dabigatran1 Rivaroxaban2,3,4 Apixaban5 Edoxaban6,7
Formulation
Issues
• CANNOT crush
capsules
• Expires 4 mo
after bottle is
opened
• CAN crush
• Mix with applesauce;
for patients with
feeding tube, mix
with water
• CAN crush
• Mix with water and
give via feeding
tube
• No information
Food
Effects5
• Take with or w/o
food
• 10-mg tablet*: take
with or w/o food
• 15-mg and 20-mg
tablets: Take with
largest meal of the
day
• Bioavailability not
affected by food
• Can be
administered
without regard
to food
1. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc.; 2014. 2. Xarelto [package insert]. Titusville, NJ: Janssen
Pharmaceuticals, Inc.; 2014. 3. Moore KT et al. Pharmacotherapy. 2012;32:e185. 4. Kubitza D et al. J Clin Pharmacol. 2006;46:549-558. 5. Eliquis
[package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 8/2014. 6. Matsushima N et al. Clin Pharmacol Drug Dev. 2013;2:358-366. 7. Mendell
J et al. J Clin Pharmacol. 2011;51:687-694.
*Not FDA approved for AF
AUC, area under the curve; GI, gastrointestinal
TSOAs: Drug-Drug Interactions
Drug Interactions/Recommendations
Dabigatran1
NVAF
• P-gp inducers (rifampin) reduce exposure to dabigatran – avoid
• Use with P-gp inhibitors in impaired renal function increases exposure
• Concomitant use of dronedarone or systemic ketoconazole:
- CrCl 30-50 mL/min–reduce dose of dabigatran to 75 mg po BID
- CrCl 15-30 mL/min–avoid use of dabigatran
Treatment and prevention of VTE/PE
• Avoid dabigatran with P-gp inhibitors if CrCl <50 mL/min
Rivaroxaban2
• Combined P-gp and CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin,
erythromycin and fluconazole) - significant increase in rivaroxaban exposure
may increase bleeding risk
• Coadministration with a combined P-gp and strong CYP3A4 inducer (e.g.,
rifampicin, phenytoin) may decrease efficacy
• Avoid concomitant use with combined P-gp and strong CYP3A4 inducers (e.g.,
carbamazepine, phenytoin, rifampin, St. John’s wort)
• Anticoagulants – avoid concomitant use
• Aspirin, NSAIDS – may increase bleeding risk
1. Pradaxa (dabigatran etexilate mesylate) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 9/2014. 2. Xarelto
(rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 9/2014
CrCl, creatinine clearance
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
Target-Specific Oral Anticoagulants
© 2014 Paradigm Medical Communications, LLC, except where noted. All rights reserved.
10
TSOAs: Drug-Drug Interactions
Drug Interactions/Recommendations
Apixaban1• Strong dual inhibitors of CYP3A4 and P-gp (ketoconazole, itraconazole,
ritonavir, or clarithromycin) increase blood levels of apixaban–for
patients on doses greater than 2.5 mg BID, reduce the dose by 50%; if
on 2.5 mg BID avoid concomitant use
• Simultaneous use of strong dual inducers of CYP3A4 and P-gp
(rifampin, carbamazepine, phenytoin, St. John’s wort) reduces blood
levels of apixaban–avoid concomitant use
Edoxaban2• Concomitant use of potent P-gp inhibitors (quinidine, verapamil,
dronedarone)–halve dose of edoxaban
1. Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Co; 8/2014. 2. Giugliano RP et al. N Engl J Med. 2013; 369:2093-
2104.
CrCl, creatinine clearance
*For dabigatran, rivaroxaban, edoxaban, patients with CrCl <30 mL/min were excluded from clinical trials; for
apixaban, patients with CrCl <25 mL/min were excluded †The 75-mg dose of dabigatran was not evaluated in clinical trials, but is an FDA-approved dose‡Dose used in clinical trials
ESRD, end stage renal disease
Drug*† Dose
Dabigatran1
• CrCl >30 mL/min: 150 mg orally BID
• CrCl 15-30 mL/min: 75 mg orally BID†
• CrCl <15 mL/min or on dialysis: dosing recommendations cannot be provided
• Dronedarone or ketoconazole in patients with CrCl 30-50 mL/min: consider reducing dose to
75 mg bid or avoid use
• P-gp inhibitors in patients with CrCl <30 mL/min: not recommended
Rivaroxaban2
• CrCl >50 mL/min: 20 mg orally QDay
• CrCl 15-50 mL/min: 15 mg orally QDay
• CrCl <15 mL/min: not recommended
Apixaban3
• 5 mg orally BID
• 5 mg orally BID in patients with NVAF and ESRD maintained on hemodialysis
• Dose adjusted to 2.5 mg orally BID for patients with ≥2 of the following: age ≥80 y, weight ≤60
kg, or SCr ≥1.5 mg/dL
Edoxaban4‡• Both doses (30 mg and 60 mg) halved if CrCl 30-50 mL/min, body weight ≤60 kg, or taking
concomitant verapamil, quinidine, or dronedarone
• Patients with CrCL <30 mL/min were excluded from ENGAGE-AF TIMI 48
TSOA: Dosing for SPAF
1. Pradaxa (dabigatran etexilate mesylate) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 9/2014. 2. Xarelto
(rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 9/2014. 3. Eliquis (apixaban) [prescribing information]. Princeton,
NJ: Bristol-Myers Squibb Co; 8/2014. 4. Giugliano RP et al. N Engl J Med. 2013;369:2093-2104.
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
Target-Specific Oral Anticoagulants
© 2014 Paradigm Medical Communications, LLC, except where noted. All rights reserved.
11
Drug* Dose
Dabigatran1
Treatment and reduction in the risk of recurrence of DVT and PE
• CrCl >30 mL/min, 150 mg orally BID after 5-10 d of parenteral anticoagulation
• CrCl < 30 mL/min or on dialysis, dosing recommendations cannot be provided
• CrCl <50 mL/min with a P-gp inhibitor, avoid use
Rivaroxaban2
Treatment of DVT, PE, and reduction in the risk of recurrence of DVT and PE
• Take 15-mg and 20-mg tablets with food; take 10-mg tablets with or without food
• 15 mg orally BID with food for the first 21 d for initial treatment of acute DVT or
PE; after the initial treatment period 20 mg orally QDay with food for remaining
treatment and long-term reduction in the risk for recurrence of DVT or PE
• 10 mg orally QDay with or without food to prevent DVT following hip or knee
replacement surgery
• CrCl <30 mL/min, avoid use
• Hip replacement surgery: recommended duration is 35 d
• Knee replacement surgery: recommended duration is 12 d
TSOA: Dosing for Recurrent DVT and PE
1. Pradaxa (dabigatran etexilate mesylate) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 9/2014.
2. Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 9/2014.
*Patients with CrCl <30 mL/min were excluded from all trials
Drug* Dose
Apixaban1
Treatment of DVT, PE, reduction in risk of recurrent DVT and PE following 6 mo of
initial therapy; prophylaxis of DVT following hip or knee replacement surgery
• 10 mg orally BID for 7 d, followed by 5 mg BID for treatment of DVT, PE
• 2.5 mg BID to prevent DVT following surgery; initial dose should be taken 12-24 h
after surgery
• 2.5 mg BID to reduce risk of recurrent DVT, PE after initial therapy
• Hip replacement surgery: recommended duration is 35 d
• Knee replacement surgery: recommended duration is 12 d
Edoxaban2†
Treatment and prevention of recurrence of VTE
• 60 mg orally QDay, taken with or without food
• 30 mg orally QDay (CrCl 30 to 50 mL/min or a body weight of 60 kg or less or in
patients who were receiving concomitant treatment with potent P-gp inhibitors)
1. Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Co; 8/2014. 2. Büller HR et al; Hokusai-VTE Investigators. N Engl J
Med. 2013;369:1406-1415.
TSOA: Dosing for Recurrent DVT and PE (continued)
*Patients with CrCl <30 mL/min were excluded from edoxaban trials; patients with CrCl <25 mL/min were excluded
from apixaban trials†Not currently approved by the US FDA for this indication.
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
Target-Specific Oral Anticoagulants
© 2014 Paradigm Medical Communications, LLC, except where noted. All rights reserved.
12
Key Points
• All 3 approved TSOAs have rapid onset and
offset
• No bridging requirement*
• Important consideration for management of
bleeding, periprocedural management
• Extent of renal clearance important
differentiator
• Dosing dependent upon renal clearance, drug-
drug interactions
*Based upon the Hokusai-VTE trial and the RE-COVER trials at least 4 days of injectable anticoagulation are required
for VTE treatment.
Oral Anticoagulation use in Stroke Prevention in Atrial Fibrillation
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
Target-Specific Oral Anticoagulants
© 2014 Paradigm Medical Communications, LLC, except where noted. All rights reserved.
13
TSOAs vs Adjusted-Dose Warfarin for SPAF
RE-LY1 ROCKET AF2 ARISTOTLE3 ENGAGE AF4
Drug Dabigatran Rivaroxaban Apixaban Edoxaban
# Randomized 18,113 14,264 18,201 21,105
Dose and
Frequency
150 mg BID
110 mg BID20 mg QD 5 mg BID
60 mg QD
30 mg QD
Dose
AdjustmentNo 20 mg – 15 mg 5 mg – 2.5 mg
60 mg – 30 mg
30 mg – 15 mg
Target INR 2.0 – 3.0 2.0 – 3.0 2.0 – 3.0 2.0 – 3.0
Design PROBE Double blind Double blind Double blind
PROBE, prospective, randomized, open-label, blinded end point evaluation
1. Connolly SJ et al. N Engl J Med. 2009;361:1139-1151. 2. Patel MR et al. N Engl J Med 2011;365:883-891. 3. Granger CB et al. N Engl J Med.
2011;365:981-992. 4. Giugliano RP et al. N Engl J Med. 2013;369:2093-2104.
Overview of Phase 3 Trials
TSOAs vs Adjusted-Dose Warfarin for SPAF
HR, hazard ratio
1. Connolly SJ et al. N Engl J Med. 2010;363:1875-1876. 2. Patel MR et al. N Engl J Med 2011;365:883-891. 3. Granger CB et al. N Engl J Med.
2011;365:981-992. 4. Giugliano RP et al. N Engl J Med. 2013;369:2093-2104.
0.5 21
Dabigatran 150 mg BID1
Rivaroxaban 20 mg QDay2*
Apixaban 5 mg BID3
Favors TSOA
Favors Warfarin
HR=0.79
HR=0.66
HR=0.88
Edoxaban 60 mg QDay4 HR=0.79
Edoxaban 30 mg QDay4 HR=1.07
All S
tro
ke o
r S
E
0.5 21
Dabigatran 150 mg BID1
Rivaroxaban 20 mg QDay2
Apixaban 5 mg BID3
Favors TSOA Favors Warfarin
HR=0.92
HR=0.94
HR=0.76
Edoxaban 60 mg QDay4HR=1.00
Edoxaban 30 mg QDay4HR=1.41
Isch
em
ic S
troke
0.1 21
Dabigatran 150 mg BID1
Rivaroxaban 20 mg QDay2
Apixaban 5 mg BID3
HR=0.26
HR=0.51
HR=0.59
Edoxaban 60 mg QDay4HR=0.54
Edoxaban 30 mg QDay4HR=0.33
Favors TSOA Favors WarfarinHem
orr
hag
ic S
tro
ke
Dabigatran 150 mg BID1
Rivaroxaban 20 mg QDay2
Apixaban 5 mg BID3
0.5 21Favors TSOA Favors Warfarin
HR=0.93
HR=1.04
HR=0.69
Edoxaban 60 mg QDay4 HR=0.80
Edoxaban 30 mg QDay4HR=0.47
0.0
Majo
r Ble
ed
ing
Favors Warfarin
All TSOAs as effective as adjusted-dose warfarin to decrease stroke or systemic
embolism with lower risk for hemorrhagic stroke
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
Target-Specific Oral Anticoagulants
© 2014 Paradigm Medical Communications, LLC, except where noted. All rights reserved.
14
TSOAs vs Adjusted-Dose Warfarin for SPAF (continued)
Outcome
(RR ±95% CI)
RE-LY1,2
(dabigatran
150 mg BID)
ROCKET-AF3
(rivaroxaban
20 mg QDay)
ARISTOTLE4
(apixaban
5 mg BID)
ENGAGE-AF5
(edoxaban
60 mg QDay)
Stroke/SE 0.65 (0.52-0.81) 0.88 (0.75-1.03) 0.79 (0.66-0.95) 0.79 (0.63-0.99)
Ischemic stroke 0.76 (0.59-0.97) 0.94 (0.75-1.17) 0.92 (0.74-1.13) 1.00 (0.83-1.19)
Hemorrhagic
stroke0.26 (0.14-0.49) 0.59 (0.37-0.93) 0.51 (0.35-0.75) 0.54 (0.38-0.77)
Major bleeding 0.94 (0.82-1.08) 1.04 (0.90-1.20) 0.69 (0.60-0.80) 0.80 (0.71-0.91)
ICH 0.40 (0.27-0.60) 0.67 (0.47-0.93) 0.42 (0.30-0.58) 0.47 (0.34 -0.63)
GI 1.50 (1.19–1.89) 1.39 (1.19–1.61) 0.89 (0.70–1.15) 1.23 (1.02–1.50)
CV mortality 0.85 (0.72-0.99) 0.89 (0.73-1.10) 0.89 (0.76-1.04) 0.86 (0.77-0.97)
All-cause
mortality0.88 (0.77-1.00) 0.85 (0.70-1.02) 0.89 (0.80-0.99) 0.92 (0.83-1.01)
1. Connolly SJ et al. N Engl J Med. 2009;363:1139-1151. 2. Connolly SJ t al. N Engl J Med. 2014;371:1464-1465. 3. Patel MR et al. N Engl J Med
2011;365:883-891. 4. Granger CB et al. N Engl J Med. 2011;365:981-992. 5. Giugliano RP et al. N Engl J Med. 2013;369:2093-2104.
Black text indicates noninferior findings
CV, cardiovascular; ICH, intracranial hemorrhage; SE, systemic embolism
SUPERIOR INFERIOR NONINFERIOR
Selecting Among Available TSOAs
Savelieva I et al. Clin Cardiol. 2013 Nov 19. [Epub ahead of print].
ACS, acute coronary syndromes; CAD, coronary artery disease
Match Specific Patient Characteristics to a TSOA with a Complementary Profile
IF the patient has… THEN consider a TSOA with…
High bleeding risk (HAS-BLED >3) Lowest bleeding risk
Previous GI bleed or high risk Lowest reported incidence of GI bleed
High risk of ischemic stroke with
low bleeding riskLowest risk for ischemic stroke
Previous stroke (secondary prevention)Evidence of greatest reduction of
secondary stroke
CAD, previous MI, or high risk for ACS/MI Positive effect in ACS
Renal impairment Less dependence on renal function
GI upset/disorders No reported GI side effects
A preference for convenient dosing Once-daily dosing
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
Target-Specific Oral Anticoagulants
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15
Key Points
• All TSOAs • Equivalent to standard warfarin based on primary outcome of
stroke or systemic embolic event
• Decreased risk for ICH, lower rates of other types of bleeding
• Strategies for selection among TSOAs based on PK/PD, comorbidities, patient preferences
Clinical pharmacists can take
an active role in selection of
the most appropriate TSOA for
individual patients, provide
patient education, and provide
ongoing management.
Oral Anticoagulation use in Deep Vein Thrombosis and Pulmonary Embolism
John Fanikos, RPh, MBA
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
Target-Specific Oral Anticoagulants
© 2014 Paradigm Medical Communications, LLC, except where noted. All rights reserved.
16
Design of TSOA VTE Trials: Acute and Chronic
Initiation
Extended
Treatment
Extended
Treatment
Initiation and Early Maintenance
Early Maintenance
DVT/PE
1. Fontana P et al. Eur Heart J. 2014;35:1836-1843. 2. Dobesh PP et al. Drugs. 2014;74:2015-2032. By permission of Oxford University Press.
A
Dabigatran
Edoxaban
B
Apixaban
Rivaroxaban
RE-COVER, RE-COVER II, HOKUSAI
EINSTEIN-DVT, EINSTEIN-PE, AMPLIFY
RE-MEDY,
RESONATE
EINSTEIN-EXT
AMPLIFY-EXT
Study DrugDuration,
mo# Pts
PE or
PE & DVT,
n (%)
Isolated
DVT,
n (%)
Unprovoked,
n (%)
Previous
VTE,
n (%)
TTR on
VKA,
%
RE-COVER
Dabigatran6 2539 786 (31) 1749 (69) Not reported 649 (26) 60
RE-COVER II
Dabigatran6 2568
815–819
(32)
1748-
1750 (68)Not reported (17.5) 57
EINSTEIN-
DVT
Rivaroxaban
3/6/12* 3449 23 (1) 3405 (99) 2138 (62) 666 (19) 58
EINSTEIN-PE
Rivaroxaban3/6/12* 4832 4832 (100) 0 (0) 3117 (65) 944 (20) 63
AMPLIFY
Apixaban6 5395 1836 (34) 3532 (65) 4845 (90) 872 (16) 61
HOKUSAI
Edoxaban3/6/12* 8240 3319 (40) 4921 (60) 5410 (66)
1520
(18)64
Efficacy/Safety for Treatment of Acute Symptomatic VTE: A Meta-Analysis
*Treatment duration defined by treating physician
TTR, time in therapeutic range; VKA, vitamin K antagonist1. van der Hulle T et al. J Thromb Haemost. 2014;12:320-328. 2. Dobesh PP et al. Drugs. 2014;74:2015-2032. © 2014 John Wiley and Sons.
Used with permission.
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
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17
OutcomePooled Absolute Risk
Difference, % (95% CI)
NNT with TSOAs to Prevent
One Event (95% CI)
Recurrent VTE -0.24 (-0.60–0.11) 417 (167–909)
Fatal PE 0.01 (-0.06–0.08) 10 000 (1667–1250)
Overall Mortality -0.10 (-0.47–0.28) 1000 (213–357)
Major Bleeding -0.67 (-1.13 to -0.21) 149 (88–476)
Non-fatal Bleeding at a
Critical Site-0.38 (-0.65 to -0.10) 263 (153–1000)
CRNM Bleeding -1.77 (- 0.340 to -0.15) 56 (29–667)
Non-Fatal ICH -0.14 (-0.31–0.03) 714 (323–3333)
Major GI Bleeding -0.16 (-0.42–0.11) 625 (238–909)
Fatal Bleeding -0.09 (-0.17–0.00) 1111 (588–0)
Efficacy/Safety for Treatment of Acute Symptomatic VTE: A Meta-Analysis (continued)
van der Hulle T et al. J Thromb Haemost. 2014;12:320-328. © 2014 John Wiley and Sons. Used with permission.
TSOAs decrease the risk for recurrent VTE and major bleeding compared to VKAs
Extended Treatment Trials for VTE Prevention
Study# Pts
Duration
Drug and
Treatment
Duration
Recurrent
VTE, %,
TSOA vs
Comparator
Major
Hemorrhage
No. Fatal
Major Bleeds
(Case Fatality
rate, %)
AMPLIFY-
Extension1*
2482
1 y
Apixaban 5 mg BID
Apixaban 2.5 mg BID
Placebo
1.7
1.7
8.8
0.1
0.2
0.5
0
0
0
EINSTEIN-
Extension2a
1196
6 or 12
mo
Rivaroxaban 20 mg
QD
Placebo
1.3
7.1
0.7
0
0
0
RE-SONATE3†1343
≥6 mo
Dabigatran 150 mg
BID
Placebo
0.4
5.6
0.3
0
0
0
RE-MEDY3†2856
6-36 mo
Dabigatran 150 mg
BID
Warfarin (INR 2-3)
1.8
1.3
0.9
1.8
0
1(4)
1. Agnelli G et al; AMPLIFY-EXT Investigators. N Engl J Med. 2013; 368:699-708. 2. The EINSTEIN-DVT Investigators. N Engl J Med.
2010;363:2499-2510. 3. Schulman S et al; RE-MEDY and RE-SONATE Trial Investigators. N Engl J Med. 2013; 368:709-718.
*Patients had undergone 6 to 12 mo of anticoagulation prior to study entry †Patients had undergone ≥3 mo of anticoagulation therapy prior to study entry
TSOAs decrease the risk for recurrent VTE vs placebo or VKA with a low risk of major hemorrhage
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
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18
TSOA Selection for VTE Prevention and Treatment
Co-morbidity or Characteristic Agent Rationale
Initial parenteral therapyDabigatran, rivaroxaban,
apixaban, edoxaban
Allowance of 48-72 h initial
treatment before randomization
Renal dysfunction (CrCl ≥ 25 mL/min to
≤ 30 mL/min)Apixaban Trial exclusion criteria
Low body weight, < 60 kg Edoxaban Trial dosing adjustment
Cancers and thrombophilia None Limited trial data
AffordabilityNone, aspirin, or
preference Similar costs
Concurrent clopidogrel Rivaroxaban Concomitant use allowed
Chronic NSAID use Apixaban Concomitant use allowed
PE with elevated biomarkers Edoxaban High-risk trial sub-populations
Compliance challenges Rivaroxaban, edoxaban Once daily dosing
Prior myocardial infarctionRivaroxaban, apixaban,
edoxaban
MI events associated with
dabigatran
Propensity for bleeding Rivaroxaban, apixaban Clinical reductions in major bleeding
Multiple meds (drug interactions) Edoxaban, apixaban Allow for dose reduction
Dobesh PP et al. Drugs. 2014;74:2015-2032.
Key Points
• Pharmacists play an important role in preventing and managing VTE
• Work with other clinicians to ensure patients receive therapies demonstrated to provide best outcomes
• Provide patient education:
• Risks for thromboembolism and bleeding and what to do in
case these events occur
• Oral and injectable anticoagulant therapy and how to
maximize outcomes with these agents
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
Target-Specific Oral Anticoagulants
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19
Addressing Clinical Challenges: Focus on Coagulation Monitoring and Management of Bleeding
Periprocedural Management of Patients on OACs
• ~250,000 pts/y in North America1,2
• ~1 in 10 pts on chronic VKAs2
• Successful use of OAC therapy in this setting requires a balance that minimizes risk for TE, risk for bleeding3
• Clinical pharmacy interventions include4:• Proper anticoagulant selection, dosage before, during,
after procedure• Pre-procedure timing of discontinuation • Careful monitoring for early bleeding signs, symptoms
• Laboratory monitoring when applicable
• Determining when to reinitiate
1. Spyropoulos AC et al. Blood. 2012;120:2954-2962. 2. Douketis JD et al. Chest. 2008;133 6 Suppl:299S-339S. 3. Nutescu EA. Am J Health-Syst Pharm.
2013;70(Suppl 1):S3-S11. 4. Dager WE. Am J Health-Syst Pharm. 2013; 70 (Suppl 1):S21-S31.
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
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20
Managing TSOAs Before Surgery or Invasive Procedures
1. Nutescu EA. Am J Health-Syst Pharm. 2013;70(Suppl 1):S3-S11. 2. Schulman S et al. Blood. 2012;119:3016-3023. 3. Pradaxa (dabigatran etexilate
mesylate) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc.; 03/2014.
Calculated CrCl, mL/min
Half-life1
Timing of Last Dose Before Surgery2,3
Standard Risk of Bleeding*
High Risk of Bleeding†
Dabigatran
≥80 11–22 h 24 h
2 d(PI: Consider longer times if major surgery, spinal puncture, spinal or epidural catheter, patients in whom complete hemostasis may
be required
50-79 12–34 h24 h
(PI: Discontinue 1-2 d before if CrCl ≥50 mL/min)
2 d
30-49 13–23 h2 d
(PI: Discontinue 3-5 d before if CrCl <50 mL/min)
4 d
<30 22–35 h 4 d 6 d
*Examples: cardiac catheterization, ablation therapy, colonoscopy without removal of large polyps, uncomplicated
laparoscopic procedures†Examples: major cardiac/cancer/urologic/vascular surgery, insertion of pacemakers/defibrillators, neurosurgery,
large hernia surgery
PI, prescribing information
Managing TSOAs Before Surgery or Invasive Procedures (continued)
Calculated CrCl, mL/min Half-life, hTiming of Last Dose Before Surgery1-4
Standard Risk of Bleeding* High Risk of Bleeding†
Rivaroxaban PI: Discontinue ≥24 h before PI: Discontinue ≥24 h before
≥80 8 24 h 2 d
50-79 9 24 h 2 d
30-49 9 1–2 d 3–4 d
<30 10 2 d 4 d
Apixaban PI: Discontinue ≥24 h before PI: Discontinue ≥48 h before
≥80 15 24 h 2 d
50-79 15 24 h 2 d
30-49 18 1–2 d 3–4 d
<30 17 2 d 4 d
Edoxaban
>80 (other data not available) 9–11 N/A N/A
1. Nutescu EA. Am J Health-Syst Pharm. 2013;70(Suppl 1):S3-11. 2. Schulman S et al. Blood. 2012;119:3016-3023. 3. Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 3/2014. 4. Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 8/2014.
*Examples: cardiac catheterization, ablation therapy, colonoscopy without removal of large polyps, uncomplicated
laparoscopic procedures†Examples: major cardiac/cancer/urologic/vascular surgery, insertion of pacemakers/defibrillators, neurosurgery,
large hernia surgery
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21
Resuming TSOAs After Procedures or Surgery • Depends solely on postoperative risk for bleeding1,2
• Risk for major bleeding clearly outweighs risk for TE1
• Major abdominal, urologic surgery: Delay TSOAs until no drainage or signs of active bleeding
• Procedures with good hemostasis shortly afterward: Resume TSOAs a minimum of 4–6 h postsurgery
• Bowel paralysis, bridging with a parenteral anticoagulant may be required
• Dabigatran, rivaroxaban, apixaban: Generally resume 24–48 h
after minor procedure; 48–72 h after major surgery if
hemostasis achieved2
• Dabigatran: Resume with half-dose (75 mg) for 1st dose, then
usual maintenance dose1
• Rivaroxaban: Resume with 10 mg, then usual maintenance
dose1
TE, thromboembolism
1. Schulman S et al. Blood. 2012;119:3016-3023. 2. Nutescu EA. Am J Health-Syst Pharm. 2013;70(Suppl 1)S2-S11.
Managing Bleeding Events:Timing of Last Dose and Renal Function
Property Dabigatran1,2 Rivaroxaban1,3 Apixaban1,4 Edoxaban5
Renal clearance of
absorbed dose, %80 36 27 35
Half-life in renal impairment, h
CrCl ≥80 mL/min 11–22 8 15
10–14CrCl 50-79 mL/min 12–34 9 15
CrCl 30-49 mL/min 13–23 9 18
CrCl <30 mL/min 22–35 10 17
“Dialyzable”
Yes
49%–57%
cleared from
plasma*
Not expected
Unlikely
(14% decrease
in exposure)
Minimal effect
1.Nutescu EA. Am J Health-Syst Pharm. 2013;70(Suppl 1):S3-11. 2. Pradaxa® (dabigatran etexilate mesylate) [prescribing information]. Ridgefield, CT:
Boehringer Ingelheim Pharmaceuticals Inc.; 9/2014. 3. Xarelto® (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.;
9/2014. 4. Eliquis® (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 8/2014.
*High-flux dialyzer, blood flow rate 200 mL/min, dialysate flow rate 700 mL/min, ~49% of total dabigatran cleared
from plasma over 4 hours and 57% with blood flow rate 300 mL/min
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
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22
Managing Bleeding Events:Risk Stratification• Minor bleeding (eg, epistaxis, ecchymosis, menorrhagia)
• Withdraw TSOA for ≥1 d; provide definitive interventions
• Restart TSOA at lower dose for short period
• Moderate bleeding (eg, upper or lower GI bleeding) • Stop anticoagulant and monitor carefully
• Consider activated charcoal* if bleeding detected w/in 2 h of TSOA ingestion
• Identify and definitively treat bleeding source
• Consider extended TSOA withdrawal • Consider low dose parenteral anticoagulant for patients at high risk of
thrombosis to allow healing
• Provide transfusion therapy (RBCs) for symptomatic anemia
• Ensure renal function stable*Dabigatran and apixaban absorption will be reduced by administration of activated charcoal; the use of activated
charcoal to reduce absorption in case of rivaroxaban overdose may be considered
GI, gastrointestinal; RBC, red blood cells
Schulman S et al. Blood. 2012;119:3016-3023.
Managing Bleeding Events:Risk Stratification (continued)
• Immediate withdrawal of anticoagulant, antiplatelet drugs
• Verify timing of last dose
• Consider activated charcoal* if bleeding detected within 2 h of TSOA ingestion1-6
• Consider offset of anticoagulant effect and renal function
• Aggressive clinical monitoring
• Transfuse packed RBCs in response to proven/anticipated severe anemia
• Consider 4-factor PCC
• Prior to administration of PCC or rVIIa, document TSOA effect and do not treat if normal values
• PT for direct factor Xa inhibitors
• aPTT for dabigatran
• Aggressively identify and treat bleeding source
• Supportive therapies
• Inotropes, ventilation, and ICU admission as needed
aPTT, activated partial thromboplastin time; ICU, intensive care unit; PCC, prothrombin complex concentrate; rVIIa,
recombinant factor VIIa
*Dabigatran and apixaban absorption will be reduced by administration of activated charcoal; the use of activated
charcoal to reduce absorption in case of rivaroxaban overdose may be considered
1. Schulman S et al. Blood. 2012;119:3016-3023. 2. Weitz JI et al. Circulation. 2012:126;2428-2432. 3. Nutescu EA. Am J Health-Syst Pharm.
2013;70(Suppl 1):S3-11. 4. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc.; 9/2014. 5. Xarelto [package insert.
Titusville, NJ: Janssen Pharmaceuticals, Inc.; 9/2014. 6. Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 8/2014.
Major and life-threatening bleeding1,2
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
Target-Specific Oral Anticoagulants
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23
Recommended Dosing of Concentrated Clotting Factor Products*
Repletion
Agent
Clotting
Factors
Replaced1,2
Dose(s) for Repletion of Specific OAC†
Warfarin1 Dabigatran1 Rivaroxaban1/Apixaban2¶
PCC3II, IX and X
(inactivated)25-50 units/kg … 50 units/kg
PCC4II, VII, IX and X
(inactivated)25-50 units/kg 25-50 units/kg 25-50 units/kg
aPCC
II, IX, X
(inactivated)
and VII
activated -
FEIBA)
500 units for INR <5 and
1000 units for INR ≥5
Up to 25 units/kg
initially with
subsequent doses
based on response1
FEIBA: 50 IE /kg up
to a max of 200
IE/kg/day3
Up to 25 units/kg initially;
no data available in
patients with active
bleeding; 80 units/kg1
FEIBA: 50 IE /kg up to a
max of 200 IE/kg/day3
rFVIIa VII (activated) 17.7-53.4 μg/kg 20-120 μg/kg 20-120 μg/kg
*None of the PCCs are indicated for the urgent reversal of anticoagulation. †Experience with doses listed in this table is limited; consult
current references and product label for most current information. ¶Limited data are available for apixaban reversal; however, it may be
rational to apply information from rivaroxaban b/c of their similar mechanisms of action.
FFP, fresh frozen plasma; PCC3, 3-factor PCC; PCC4, 4-factor PCC
1. Nutescu EA et al. Am J Health Syst Pharm. 2013;70:1914-1929. ©2013, American Society of Health-System Pharmacists, Inc. All rights reserved.
Reprinted with permission. 2. Babilonia K et al. Thromb J. 2014; Apr 17;12:8. doi: 10.1186/1477-9560-12-8. eCollection 2014. 3. Heidbuchel H et al.
Europace. 2013;15:625-651.
4-Factor PCC: Individualize Dosing
Pre-treatment INR 2–<4 4–6 >6
Dose* (units of Factor
IX)/kg body weight 25 35 50
Maximum dose† (units of
Factor IX)
Not to exceed
2500
Not to exceed
3500
Not to
exceed 5000
Dosing is based on body weight. Dose based on actual potency as stated on the carton, which will vary
from 20-31 Factor IX units/mL after reconstitution. Nominal potency is 500 or 1000 units per vial,
approximately 25 units per mL after reconstitution.
*Units refer to international units†Dose is based on body weight ≤100 kg. For patients weighing >100 kg, maximum dose should not be exceeded.
KCentra (Prothrombin Complex Concentrate [Human]) [prescribing information]. Kankakee, IL: CSL Behring LLC; Dec. 2013.
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24
TSOAs: Antidotes in Development1
Target Mechanism of ActionInvestigation
Status
Idarucizumab Dabigatran
Humanized Fab: specifically binds dabigatran
(binding affinity ~350 x higher than binding of dabigatran to thrombin)
Bleeding patients and surgical
patients2
Andexanet alfa (PRT064445)
FXa inhibitors
Recombinanthuman FXa variant: competitive affinity for direct FXa inhibitors
Healthy volunteers3,4
Aripazine (PER977)
UniversalSynthetic small molecule:
charge-charge interactions (heparin); hydrogen bonds (TSOAs)5
Phase I6
1. Lauw M et al. Can J Cardiol. 2014; doi: 10.1016/j.cjca.2014.01.015; 2. Clinicaltrials.gov: NCT02104947. 3. Clinicaltrials.gov: NCT02220725. 4. Clinicaltrials.gov: NCT02207725. 5. Bakhru S et al. AHA 2013; abstr 11395. 6. Perosphere. Latest News:Perosphere and Daiichi Sankyo Enter into a Clinical Trial Agreement to Evaluate the Efficacy and Safety of PER977 to Reverse the Anticoagulant Activity of the Investigational, Oral, Once-Daily Factor XA Inhibitor Edoxaban. www.perosphere.com/content/news/httpwww.perosphere.comcontentnewsreleases042513.htm. Accessed 11/17/14.
Clinical Pharmacy Call to Action: Ensuring Appropriate Anticoagulation
Sarah Spinler, PharmD, FCCP, FCPP, FAHA, FASHP, AACC,BCPS–AQ Cardiology
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
Target-Specific Oral Anticoagulants
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25
Clinical Pharmacy Call to Action:ASHP Statement 2012
Pharmacist’s Leadership Role in Anticoagulation
Therapy Management
• Advocate for role in development, implementation,
monitoring, and assurance of continuity of care
• Coordinate individualized care within anticoagulation
management programs
• Encourage pharmacist programs to educate stakeholders on
anticoagulant medication use, drug interactions, adverse
events, importance of adherence, and monitoring
ASHP. Medication Therapy and Patient Care: Organization and Delivery of Services–Positions.
www.ashp.org/DocLibrary/BestPractices/OrganizationPositions.aspx. Accessed 11/12/14.
ASHP Anticoagulation Resource Center
“Anticoagulation is high risk therapy involving complex dosing, monitoring, and ensuring patient adherence with outpatient therapy. Regulations have demonstrated the need for pharmacist involvement with anticoagulation patient management.”
http://www.ashp.org/anticoagulation
American Society of Health-System Pharmacists. Anticoagulation Resource Center. www.ashp.org/anticoagulation. Accessed 11/14/14.
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
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26
The Anticoagulation Forum
• Mission
• To offer insight and expertise to those of you on the front lines
• Goals
• To have a community where physicians, pharmacists, and nurses can come to find the latest research, engage in educational programs, and find tools to evaluate and enhance their practice
• Ultimate goal, to provide a resource where practice changing, evidence-based information is readily available
• Anticoagulation Forum Centers of Excellence Resources
• Quality improvement organizations dedicated to reducing anticoagulation adverse events – eg, The New York Anticoagulation Coalition
http://acforum.org/
The Anticoagulation Forum. http://acforum.org/#&panel1-2. Accessed 11/14/14.
Take-Home Points
• Take an active role in anticoagulation management
• Remember how to use anticoagulants
• Consider trial design, drug-drug, drug-food interactions when selecting a TSOA
• Understand strategies for the management of bleeding events
• Keep up with current product labeling and data
Remember, you are the medication experts!
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
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27
Interactive Case Review and Panel Discussion
JB, 71-Year-Old White Female With NVAF
• Presents to cardiologist for annual follow-up
• Past medical history• NVAF x 4 years• Hypertension x 18 years• Osteoarthritis
• Lives alone but still drives and is active volunteering in the community
• Medications• Warfarin 2.5 mg alternating with 5 mg every other day• Hydrochlorothiazide 50 mg po q day• Diltiazem XR 120 mg po BID• Dofetilide 500 mcg po BID• Calcium and vitamin D po BID• Multivitamin po q day• Ibuprofen 400 mg po tid prn pain
• INR variable, ranging from 1.4 to >3 on 2 occasions in last 6 mo
• Current labs:• Renal function normal• INR: 2.8
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28
Panel Discussion• What are the risks/benefits of continuing warfarin?
• What are JB’s modifiable risk factors for bleeding? Falling?
• Which TSOA would you choose for this patient? Why?
• What is the appropriate dose of the selected agent for JB?
JB, 71-Year-Old White Female With NVAF
JB, 71-Year-Old White Female With NVAF
• 9 mos later JB presents to ED (driven by daughter) fainting and falling at home
• Patient in AF, no acute distress, but significant bleeding from a deep forehead laceration
• Vital signs:
• T: 98.9°F
• P: irregular, 92
• BP: 132/76 mm Hg
• RR: 18/min
• Pertinent laboratory values
• Hg: 14.4 g/dL
• SCr: 1.1 mg/dL (est CrCl = 63 ml/min)
• INR: 1.6
• Her daughter says JB’s last dose of TSOA was about 4 hours ago
ED, emergency department
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29
Panel Discussion
• What is JB’s CHA2DS2-VASc score?
• HAS-BLED = 3
• How would you manage this bleeding episode?
• What are JB’s modifiable risk factors for bleeding? Falling?
• Would you continue treatment with a TSOA in this patient?
JB, 71-Year-Old White Female With NVAF
1. Lahaye S et al. Thromb Haemost. 2014;111(3):465-473; online Suppl 2: 111.4. 2. Lip GYH, et al. Chest. 2010; 137: 263-272.Reproduced with
permission from the American College of Chest Physicians.
1,2
JB, 71-Year-Old White Female With NVAF
• JB presents for follow-up visit at the outpatient anticoagulation clinic 3 mo later
• Taking dabigatran 150 mg PO BID
• Denies problems and any bleeding events
• Reports adherence to dabigatran; this is confirmed by Rx refill history
• Note that she is having a cardiac ablation in 2 weeks, wants to know if she should keep taking her dabigatran
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
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30
GJ, 52-Year-Old Woman With Post-op Calf Pain
Medical History
• Longstanding hypertension
Clinical Course
• Extensive L medial meniscus injury requiring arthroscopic surgical repair
• Postop day #3: New L calf discomfort and presented to ED at 04:00 AM Monday complaining of severe L calf pain
• Ultrasound performed at 8:00 AM Monday morning; isolated L calf vein thrombosis was detected
• Pertinent laboratory values
• SCr: 0.9 mg/dL
• BUN: 12 mg/dL
Clinical Course (continued)
• Two days later GJ collapsed at work, transported to ED via ambulance
• ECG showed new onset AF with a rapid ventricular response of 130/m
• BP: 94/62 mm Hg
• T: 97.8°F
• Arterial oxyhemoglobin saturation: 88%
• Massive PE confirmed on chest CT scan
• Unfractionated heparin 10,000 U IV bolus, then continuous infusion of 1250 units/h
• Follow-up ECG showed reversion from AF to sinus tachycardia, at 115/m
• Heparin infusion rate decreased by 50%
• Catheter-directed thrombolysis performed successfully cardiac cath lab
• No bleeding complications
GJ, 52-Year-Old Woman With Post-op Calf Pain
ECG, electrocardiograph; CT, computed tomography; TPA, tissue plasminogen activator
Answering the Call: The Role of Health-System Pharmacists to Improve Use of
Target-Specific Oral Anticoagulants
© 2014 Paradigm Medical Communications, LLC, except where noted. All rights reserved.
31
Panel Discussion• How would you transition treatment with a goal of
hospital discharge on day 3?
• How long should oral anticoagulation be continued?
• What ongoing monitoring is important in this case?
GJ, 52-Year-Old Woman With Post-op Calf Pain
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