Updates in Anticoagulation...Updates to Venous Thromboembolism (VTE) Guidelines CHEST. 2016; 149(2):...
Transcript of Updates in Anticoagulation...Updates to Venous Thromboembolism (VTE) Guidelines CHEST. 2016; 149(2):...
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Updates in Anticoagulation
Megan Labreck, PharmD, BCPS, CACP
Kristian Navickas, PharmD, BCPS, BCACP
Tara Schreck, PharmD, BCACP
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Pharmacist Learning Objectives
At the end of this program, the learner will be able to:
1. Discuss the updates to the 2016 CHEST Guidelines on
Antithrombotic Therapy for VTE Disease
2. Review the current indications and dosing for NOACs
3. Explore the emerging roles of NOACs in CAD, PCI, and
cardioversion
4. Review the updates to the ACC recommendations on the
management of bleeding in patients on oral anticoagulation
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Pharmacy Technician Objectives
At the end of this program, the learner will be able to:
1. Understand the similarities and differences
between oral anticoagulants
2. Identify the generic and brand names for oral
anticoagulants
3. State the contraindications to oral anticoagulants
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Patient Case
• BC is a 26 yo male diagnosed with a DVT in his left popliteal vein.
• PMH includes a h/o HTN, treated with lisinopril10mg daily (patient admits to non-adherence)
• Patient has commercial insurance through his employer
• Patient admits he recently returned from a trip to New Zealand (spent 20+ hours on airline)
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Patient Case
• Things to consider:
– Cause of VTE
– Insurance
– Adherence to medications
• Decisions to make:
– Choice of therapy
– Duration of therapy
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A Brief History of Oral
Anticoagulants
• 1930s –
• 1951 – Suicide attempt draws attention to warfarin’s clinical effects
• 1954 – Coumadin approved by Endo Pharmaceuticals
• 1955 – Warfarin given to President Eisenhower after heart attack
• 1980s – INR developed, optimal range introduced
• 1990s – Optimal anticoagulation duration introduced
The Pharmaceutical Journal, Vol. 284, p189 | URI: 10997264
BJH. 2008; 141: 757-761
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A Brief History of Oral
Anticoagulants (AC), cont.
• 2000s – First NOACs developed: direct thrombin
inhibitors (DTIs) and Factor Xa inhibitors (FXaIs)
– Ximelagatran halted in 2006 due to liver toxicity
– Dabigatran approved in 2010
– Rivaroxaban approved in 2011
– Apixaban approved in 2012
– Edoxaban approved in 2015
The Pharmaceutical Journal, Vol. 284, p189 | URI: 10997264
BJH. 2008; 141: 757-761
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Keeping Safety in Mind
• Joint Commission 2018 National Patient Safety Goals:– NPSG.03.05.01 – Reduce the likelihood of patient harm
associated with anticoagulant therapy
– Use approved protocols for initiation/maintenance
– Baseline INR must be obtained for patients on warfarin, and policies in place for monitoring of anticoagulation
– Provide education regarding anticoagulant therapy to prescribers, staff, patients, and caregivers
The Joint Commission. 2018. https://www.jointcommission.org
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Updates to Venous
Thromboembolism (VTE)
Guidelines
CHEST. 2016; 149(2): 315-352
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2016 CHEST VTE Guidelines:
Select Key ChangesTopic New Changed New evidence but
no change
Choice of long-term
and extended AC
therapy
ASA for extended
treatment of VTE
Management of
recurrent VTE on
AC therapy
Duration of
treatment
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VTE Risk Factors
• Surgery
• Trauma
• Increasing age
• Obesity
• History VTE
• Cancer
• Immobility
• Pregnancy
• Estrogen-containing oral contraceptives or hormone replacement
• Inherited or acquired thrombophilia
CHEST. 2016; 149(2): 315-352
Photo credit: American Society of Hematology
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Choice of AC Therapy - Acute & Long-
Term
• Deep vein thrombosis (DVT) of leg or pulmonary embolism (PE) without active cancer– Extended treatment with NOACs reduce recurrent VTE and is
associated with less bleeding risks
– NOACs preferred over warfarin (Grade 2B)• No one NOAC is preferred over the other
• Rivaroxaban, apixaban (No bridging needed)
• Dabigatran, edoxaban (Start with parenteral AC x5d)
• Warfarin preferred over LMWH (Grade 2C)– Overlap with parenteral anticoagulation x5 days and INR >2 for
24 hours
CHEST. 2016; 149(2): 315-352
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Choice of AC Therapy - Acute & Long-
Term, Cont.
• DVT of leg or PE with active cancer
– LMWH preferred over warfarin (Grade 2C)
– LMWH preferred over NOACs (Grade 2C)
– In patients with VTE and cancer who are not treated
with LMWH, there is no preference for either a NOAC
or VKA
CHEST. 2016; 149(2): 315-352
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Choice of AC Therapy - Extended
Therapy
• No need to change choice of AC after the first 3
months
• Reassess in periodic intervals
– Annually
• Risk vs Benefit Consideration
– Reduction in recurrent VTE
CHEST. 2016; 149(2): 315-352
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AC Considerations for
Initial and Long-Term TreatmentFactor Preferred AC
Cancer LMWH
Parenteral therapy to be avoided Rivaroxaban; apixaban
Once daily oral therapy preferred Rivaroxaban; edoxaban; warfarin
Liver disease and coagulopathy LMWH
Renal disease; CrCl <30mL/min Warfarin
Coronary Artery Disease Warfarin; rivaroxaban; apixaban; edoxaban
Dyspepsia or h/o GI bleeding Warfarin; apixaban
Poor adherence Warfarin
Reversal agent needed Warfarin; UFH
Pregnancy or risk of pregnancy LMWH
Cost Varies
CHEST. 2016; 149(2): 315-352
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NOAC Trials in VTE Treatment
ComparisonDabigatran Rivaroxaban Apixaban Edoxaban
Trials RECOVER I
RECOVER II
EINSTEIN DVT
EINSTEIN PE
AMPLIFY HOKUSAI VTE
Study Design Randomized,
double-blind, non-
inferiority, parallel
group
Randomized,
open-label,
event-driven, non-
inferiority, parallel
group
Randomized,
double-blind,
parallel group
Randomized,
double-blind, non-
inferiority parallel
group
Primary Efficacy
Endpoint
Recurrent
symptomatic VTE
or death related
VTE
Recurrent
symptomatic VTE
Recurrent
symptomatic VTE
or death related
VTE
Recurrent
symptomatic VTE
Primary Safety
Endpoint
Major bleeding Major or CRNM
bleeding
Major bleeding Major or CRNM
bleeding
Drugs. 2014;74:2015-32.
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NOAC Trials in VTE Treatment
ComparisonDabigatran Rivaroxaban Apixaban Edoxaban
Sample Size (n) 5107 8281 5395 8240
% DVT Patients 69% 99% (EINSTEIN DVT) 66% 60%
% PE Patients 22% 75% (EINSTEIN PE) 25% 30%
% PE and DVT
Patients
9% 15% 9% 10%
% Active Cancer 4% 5% 3% 3%
% Unprovoked N/A 63% 90% 66%
Drugs. 2014;74:2015-32.
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NOAC Trials in VTE Treatment
ComparisonDabigatran Rivaroxaban Apixaban Edoxaban
Intervention 150mg BID
150mg BID
15mg BID x21
days → 20mg
once daily
10mg BID x7 days
→ 5mg BID
60mg or 30mg
once daily
Comparator Warfarin Enoxaparin →
warfarin
Enoxaparin →
warfarin
Warfarin
Parenteral AC (UFH, LMWH,
fondaparinux)
Mandatory, ≥5 day Optional, max 48h Optional, max 36h Mandatory, ≥5 day
Duration of
Treatment
6 mos 3, 6, or 12 mos 6 mos 3, 6, or 12 mos
Drugs. 2014;74:2015-32.
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NOAC Trials in VTE Treatment
ComparisonDabigatran Rivaroxaban Apixaban Edoxaban
Primary efficacy
endpoint (%)
2.4 vs 2.1
2.3 vs 2.2
2.1 vs 3
2.1 vs 1.8
2.3 vs 2.7 3.2 vs 3.5
Major Bleeding
(%)
1.6 vs 1.9
1.2 vs 1.7
0.8 vs 1.2
1.1 vs 2.2
0.6 vs 1.8 1.4 vs 1.6
CRNM Bleeding
(%)
4 vs 6.9
3.8 vs 6.2
7.3 vs 7
9.5 vs 9.8
3.8 vs 8 7.2 vs 8.9
Major and CRNM
Bleeding (%)
5.6 vs 8.8
5 vs 7.9
8.1 vs 8.1
10.3 vs 11.4
4.3 vs 9.7 8.5 vs 10.3
Drugs. 2014;74:2015-32.
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Aspirin (ASA) for Extended
treatment of VTE
• In patients with an unprovoked DVT or PE who are stopping AC treatment and have no contraindication to ASA:– ASA preferred over no ASA (Grade 2C)
– Study population = patients completing 3 months of initial AC therapy after 1st unprovoked DVT/PE
– Less effective at preventing recurrent VTE than anticoagulants
– Balance with ASA’s risk of bleeding and inconvenience
– Better than no therapy
CHEST. 2016; 149(2): 315-352.
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Management of VTE Despite AC
Therapy
• If on therapeutic warfarin or NOAC, then switch to LMWH temporarily (minimum 1 month) (Grade 2C)
• If on long-term LMWH and compliant, recommendation is to increase the dose by 25-33% (Grade 2C)
• Reason for recurrence– Non-adherence
– Subtherapeutic warfarin
– Drug interaction (reducing AC effect)
– Patient factors (active cancer, antiphospholipid syndrome, hormones)
CHEST. 2016; 149(2): 315-352.
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Duration of AC Treatment Based on
Type of VTEType of VTE Recommended Duration of
Treatment 2012
Recommended Duration of
Treatment 2016
Proximal DVT (leg) or PE
provoked by surgery
3 months 3 months
DVT (leg) or PE provoked by
nonsurgical transient risk factor
3 months 3 months
Isolated distal DVT (leg)
provoked by surgery or
nonsurgical transient risk factor
3 months 3 months
Unprovoked PE or DVT (leg) At least 3 months At least 3 months
Pt’s first DVT that is an
unprovoked proximal DT (leg)
or PE
At least 3 months Extended therapy (no
scheduled stop date)
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Duration of AC Treatment Based on
Type of VTEType of VTE Recommended Duration of
Treatment 2012
Recommended Duration of
Treatment 2016
In patients with second
unprovoked VTE with a low
bleeding risk
Recommended extended
therapy
Extended therapy (no scheduled
stop date)
In patients with second
unprovoked VTE with a
moderate bleeding risk
Suggested extended therapy At least 3 months
In patients with second
unprovoked VTE with a high
bleeding risk
Suggest 3 months 3 months
Patients with DVT (leg) and
active cancer w/ or w/o high risk
of bleeding
Extended therapy Extended therapy (no scheduled
stop date)
CHEST. 2016; 149(2): 315-352.
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Review: NOAC Indications
and Dosing
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PHOTO CREDIT:
HTTPS://WWW.NATURE.COM
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NOAC: Renal Exclusions
• Dabigatran:
– Avoid in CrCl <15 mL/min
• Rivaroxaban:
– Avoid non-valvular AF treatment in CrCl <15 mL/min
– Avoid DVT/PE treatment and prophylaxis in CrCl <30
mL/min
Pradaxa (dabigatran) [prescribing information]. Ridgefield, CT:
Boehringer Ingelheim Pharmaceuticals, Inc; August 2014.
Xarelto (rivaroxaban) [prescribing information]. Gurabo, PR:
Janssen Pharmaceuticals Inc; September 2014.
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NOAC: Renal Exclusions
• Apixaban:
– DVT/PE Treatment excluded CrCl <25 mL/min or SCr>2.5 from trials
– DVT prophylaxis excluded CrCl <30 mL/min from trial
• Edoxaban:
– Avoid non-valvular AF treatment in CrCl <15 mL/min or >95 mL/min
– Avoid DVT/PE treatment in CrCl <15 mL/min
Eliquis (apixaban) [prescribing information]. Princeton,
NJ: Bristol-Myers Squibb; March 2014.
Savaysa (edoxaban) [prescribing information]. Tokyo,
Japan: Daiichi Sankyo; January 2015.
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NOAC: Half-Life
• T1/2 much shorter than warfarin
– Compliance is crucial to NOAC success
Dabigatran Apixaban Edoxaban Rivaroxaban
T1/2 (hours) 12-17 12 10-14 9-13
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Cost Comparison; Monthly
• Dabigatran: $387
• Rivaroxaban: $425
• Apixaban: $425
• Edoxaban: $342
• Warfarin: $4
• PT/INR (self pay): $17.55
Drug prices obtained from www.goodrx.com
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Betrixaban – New NOAC
• Direct factor Xa inhibitor
• Indication: VTE prevention– Acutely ill medical, non-surgical patients
– Moderate or severely limited mobility plus other VTE risk factors
• Not recommended for use in AF, VTE treatment, after hip/knee surgery, long-term VTE prevention in cancer or prior VTE
Product information for Bevyxxa. Portola Pharmaceuticals.
South San Francisco, CA 94080. March 2018.
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Betrixaban – New NOAC
• LMWH → 160mg x1 then 80mg once daily with food for 35-42 days
• Renal dosing: 80mg x1 then 40mg once daily with food for 35-42 days
• APEX clinical trial – prevents small number of symptomatic VTEs, increases risk of CRNM
• Expensive ($630 for 6 weeks therapy)
Product information for Bevyxxa. Portola Pharmaceuticals.
South San Francisco, CA 94080. March 2018.
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Emerging Roles of NOACs
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NOACs in CAD: COMPASS Trial
• Clinical question
– In patients with established stable atherosclerotic
disease, is rivaroxaban plus aspirin more effective
than aspirin alone in reducing cardiovascular
death, stroke, or nonfatal MI?
NEJM. 2017; 377(14): 1319-1330.
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NEJM. 2017; 377(14): 1319-1330.
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COMPASS Summary
• Rivaroxaban dose is vascular dose
• Rivaroxaban 2.5mg twice daily + aspirin 100mg
daily
– Reduces CV death, stroke, MI
– Increases major bleeding without a significant
increase in fatal or intracranial bleeding
– No significant benefit vs. rivaroxaban alone
NEJM. 2017; 377(14): 1319-1330.
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COMPASS Summary
• Rivaroxaban dose is vascular dose
• Rivaroxaban 2.5mg twice daily + aspirin 100mg
daily
– Reduces CV death, stroke, MI
– Increases major bleeding without a significant
increase in fatal or intracranial bleeding
– No significant benefit vs. rivaroxaban alone
NEJM. 2017; 377(14): 1319-1330.
Take Away:
Rivaroxaban dose is not approved worldwide
Early termination: this may overestimate the
degree of benefit of riva+aspirin
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NOACs in PCI: RE-DUAL PCI
• Clinical question– In patients with nonvalvular atrial fibrillation (AF)
undergoing percutaneous coronary intervention (PCI) for coronary artery disease, is dual therapy with a thienopyridine antiplatelet and dabigatran associated with less bleeding when compared to triple therapy with aspirin, a thienopyridine antiplatelet, and dabigatran? Is dual therapy associated a higher rate of thrombosis?
NEJM. 2017; 377(16): 1513-1524.
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NEJM. 2017; 377(16): 1513-1524.
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RE-DUAL PCI: Summary
• In AF patients who underwent PCI– Dabigatran + P2Y12 (dual therapy) antagonist significantly reduced risk of
bleeding vs. warfarin triple therapy
– Non-inferiority for thrombotic events
– Dabigatran doses used are (110mg vs 150mg) approved worldwide for stroke prevention
• LIMITATIONS– The initial goal sample size of 8520 patients (powered to assess for
thromboembolic events) was not reached due to feasibility. As a result, the trial is underpowered to robustly assess for thrombotic events.
– Only 12% of study patients received ticagrelor, limiting generalizability of these findings to use of this drug.
NEJM. 2017; 377(16): 1513-1524.
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RE-DUAL PCI: Summary
• In AF patients who underwent PCI– Dabigatran + P2Y12 (dual therapy) antagonist significantly reduced risk of
bleeding vs. warfarin triple therapy
– Non-inferiority for thrombotic events
– Dabigatran doses used are (110mg vs 150mg) approved worldwide for stroke prevention
• LIMITATIONS– The initial goal sample size of 8520 patients (powered to assess for
thromboembolic events) was not reached due to feasibility. As a result, the trial is underpowered to robustly assess for thrombotic events.
– Only 12% of study patients received ticagrelor, limiting generalizability of these findings to use of this drug.
NEJM. 2017; 377(16): 1513-1524.
Take Away:
Dabigatran + P2Y12 (dual therapy) is non-inferior
to triple therapy and may be an option in AF
patients undergoing PCI
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NOACs in PCI: PIONEER-AF PCI
• Clinical question
– Among patients with nonvalvular AF undergoing PCI
with stent placement, does low-dose rivaroxaban plus
either single or dual antiplatelet therapy reduce risk of
bleeding when compared to warfarin plus dual
antiplatelet therapy?
NEJM. 2016; epub Nov 2016: 1-12.
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NEJM. 2016; epub Nov 2016: 1-12.
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PIONEER-AF PCI Summary
• In patient with AF undergoing PCI for stent placement– Rivaroxaban based therapy was associated with less clinically
significant bleeding
– TIMI major bleeding was similar between the three groups
– Major ADE (ie: cardiac events, stent thrombosis) was similar between groups
– All cause mortality and re-hospitalization was lower with rivaroxaban vs. warfarin/DaPT
• Limitations– Not blinded, not powered for efficacy, smaller sample size than
NOAC trials
NEJM. 2016; epub Nov 2016: 1-12.
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PIONEER-AF PCI Summary
• In patient with AF undergoing PCI for stent placement– Rivaroxaban based therapy was associated with less clinically
significant bleeding
– TIMI major bleeding was similar between the three groups
– Major ADE (ie: cardiac events, stent thrombosis) was similar between groups
– All cause mortality and re-hospitalization was lower with rivaroxaban vs. warfarin/DaPT
• Limitations– Not blinded, not powered for efficacy, smaller sample size than
NOAC trials
NEJM. 2016; epub Nov 2016: 1-12.
Take Away:
Rivaroxaban based therapy had less clinically
significant bleeding compared to VKA based
therapies.
Not powered for efficacy- is this clinically
significant?
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NOACs in Cardioversion: EMANATE
• Clinical Question:
– The goal of the trial was to evaluate short-duration
apixaban compared with warfarin with among patients
undergoing cardioversion.
Am Heart Journal. 2016; 179: 59-68.
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Am Heart Journal. 2016; 179: 59-68.
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Am Heart Journal. 2016; 179: 59-68.
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EMANATE Trial Summary
• Bleeding rates were similar across both the
apixaban and warfarin groups.
• EMANATE was underpowered
– Their findings “support the use of apixaban in patients
with AFib undergoing cardioversion.”
Am Heart Journal. 2016; 179: 59-68.
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EMANATE Trial Summary
• Bleeding rates were similar across both the
apixaban and warfarin groups.
• EMANATE was underpowered
– Their findings “support the use of apixaban in patients
with AFib undergoing cardioversion.”
Am Heart Journal. 2016; 179: 59-68.
Take Away:
This study supports the use of apixaban prior to
cardioversion.
Stay tuned for full publication
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Managing Bleeding
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New Guidance for Managing
Bleeding
• American College of Cardiology (ACC) released expert consensus decision pathway in 2017
• Provides guidance to clinicians who are managing bleeding in the setting of warfarin and NOACS
• Considers:– Severity of bleeding
– Acute medical and surgical management
– Need for reversal
– Appropriateness of restarting anticoagulation
JACC. 2017; 70(24): 3042-4067
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Assessment and Treatment
Strategies
• Major bleeding:– Bleeding at critical site
– Hemodynamically unstable
– Clinically overt bleeding
• Minor bleeding: Everything else
• Treatment recommendations:– Major bleeding: Stop OAC, initiate appropriate measures to stop
bleeding
– Minor bleeding: Stop OAC in patients requiring hospitalization, a surgical intervention, or a transfusion
JACC. 2017; 70(24): 3042-4067
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Laboratory Assessment
• All anticoagulated patients: PT and aPTT
• VKA: INR
• Dabigatran: Dilute thrombin time, ecarin clotting time, ecarin chromogenic assay– Thrombin time (TT): Normal value can rule out relevant
dabigatran levels
• FXa-Inhibitors: Chromogenic anti-Xa assay, PT (edoxaban and rivaroxaban)
JACC. 2017; 70(24): 3042-4067
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Assessment and Treatment
Strategies
VKA (Warfarin) DTI (Dabigatran)
FXa-Inhibitors (Apixaban,
edoxaban, rivaroxaban)
-Vitamin K oral (non-major) or
IV (major/critical)
-Consider activated charcoal
for ingestion w/in 2-4 hours
-Consider activated charcoal
for ingestion w/in 2-4 hours
-Administer 4F-PCC
-INR 2-4: 25u/kg
-INR 4-6: 35u/kg
-INR >6: 50u/kg
-Administer 5g idarucizumab
IV
-Administer 4F-PCC 50u/kg IV
- Alternative 4F-PCC dosing
-Low fixed-dose option
(1000units)
-1500u for ICH
-If idarucizumab IV not
available, administer 4F-PCC
or aPCC 50u/kg IV
-If 4F-PCC not available,
administer aPCC 50u/kg IV
JACC. 2017; 70(24): 3042-4067
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Patient Case – Remember BC?
• Things to consider:
– Cause of VTE – likely related to his travel (provoked
cause)
– Insurance (high-deductible not met)
– Patient endorses a desire to improve adherence and
overall health, thinks he might be more successful
with once-daily therapy.
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Patient Case – Remember BC?
• Which choice of therapy is recommended for BC
at this time?
A. Weight-based LMWH
B. Warfarin
C. NOAC (no specific agent preferred)
D. NOAC (specific agent preferred)
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Patient Case – Remember BC?
• Which duration of anticoagulation therapy is
recommended for BC at this time?
A. Indefinite
B. At least 3 months
C. At least 1 year
D. At least 2 weeks, then reevaluate
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Patient Case – Remember BC
• Should BC be on ASA after his anticoagulation therapy is complete?– Guidelines recommend after first 3 months (grade 2C)
– Studies involved 1st unprovoked VTE
• Does BC need bridging with LMWH prior to starting oral anticoagulation?– No – rivaroxaban, apixaban
– Yes – dabigatran, edoxaban
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Updates in Anticoagulation
Megan Labreck, PharmD, BCPS, CACP
Kristian Navickas, PharmD, BCPS, BCACP
Tara Schreck, PharmD, BCACP
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Betrixaban – New NOAC
• Direct factor Xa inhibitor
• Indication: VTE prevention– Acutely ill medical, non-surgical patients
– Moderate or severely limited mobility plus other VTE risk factors
• Not recommended for use in AF, VTE treatment, after hip/knee surgery, long-term VTE prevention in cancer or prior VTE
Product information for Bevyxxa. Portola Pharmaceuticals.
South San Francisco, CA 94080. March 2018.
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Betrixaban – New NOAC
• LMWH → 160mg x1 then 80mg once daily with food for 35-42 days
• Renal dosing: 80mg x1 then 40mg once daily with food for 35-42 days
• APEX clinical trial – prevents small number of symptomatic VTEs, increases risk of CRNM
• Expensive ($630 for 6 weeks therapy)
Product information for Bevyxxa. Portola Pharmaceuticals.
South San Francisco, CA 94080. March 2018.