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The Blood Thins and the Plot Thickens
American College of Physicians Annual Scientific Meeting
November 7, 2014
Allison Burnett, PharmD, CACP, PhC
Clinical Assistant Professor- UNM College of Rx
Team Lead- Inpatient Anticoagulation Services
University of New Mexico Hospital
•
Anticoagulation Forum
Board member
Honoraria
•
Society of Hospital Medicine (SHM)
Honoraria
•
Island Peer Review Organization (IPRO)
Honoraria
•
•
•
•
Appropriate patient selection
Laboratory measurement
Peri-procedural management
Switching between agents
Management of severe bleeding
Appropriate patient selection
Laboratory measurement
Peri-procedural management
Switching between agents
Management of severe bleeding
Which of the following patients would be considered a good
candidate for TSOAC therapy?
A. 64-year-old male with a St. Jude’s mechanical mitral valve
B. 65-year-old female with diabetes & hypertension
(both well-controlled with medication), normal kidney
function and new onset atrial fibrillation
C. 37-year-old female with end-stage renal disease, on
hemodialysis, who has thrombosed her dialysis fistula
D. 54-year-old male with a history of recurrent VTE and
labile INR due to non-compliance with warfarin therapy
Adapted from Weitz JI, Bates SM. J Thromb Haemost 2005; 3: 1843-53.
EU
US
Canada
Rivaroxaban
(Xarelto®)
NVAF
VTE PPX
VTE TX
ACS
NVAF
VTE PPX
VTE TX
NVAF
VTE PPX
VTE TX
Apixaban
(Eliquis®)
NVAF
VTE PPX
NVAF
VTE PPX
VTE TX
NVAF
VTE PPX
Dabigatran
(Pradaxa®)
NVAF
VTE PPX
VTE TX
NVAF
NVAF
VTE PPX
Edoxaban
(Lixiana®)
Japan
VTE TX
VTE PPX
Siegal DM, et al. J Thromb Thrombolysis 2013; 35: 391-98.
Agent
ACS = acute coronary syndrome; NVAF = non-valvular atrial fibrillation; PPX = prophylaxis; TX = treatment;
VTE = venous thromboembolism
Agent
Warfarin
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
IIa, VIIa, IXa, Xa
IIa
Xa
Xa
Xa
4-5 days
1.5-3 h
2-4 h
1-3 h
1-2 h
Half-life
40 h
12-17 h
5-9 h
9-14 h
9-11 h
Renal elim.
None
80%
33%
25%
35-50%
Dialyzable
No
Yes
No
No
No
Interactions
Many
P-gp
3A4, P-gp
3A4, P-gp
3A4, P-gp
Monitoring
Yes
No
No
No
No
Vitamin K
No
No
No
No
INR
aPTT (qual)
PT (qual)
No data
PT (qual)
Target
Peak effect
Antidote
Lab measure
P-gp = p glycoprotein
3A4 = cytochrome P450 3A4
qual = qualitative
Cove CL, Hylek EM. J Am Heart Assoc. 2013; 2:e000136.
•
Improved pharmacokinetic/pharmacodynamic profile
– Rapid onset/offset of action
– Fewer dietary and drug interactions
– Wide therapeutic window allows fixed dosing
– No need for routine monitoring
•
Greater convenience and patient satisfaction
•
Improved safety profile
•
Potentially more cost-effective
Bauer KA. ASH Education Book 2013; 1:464-470
Ruff CT, et al. Lancet 2013; 383 (9921): 955-62
•
Dose reduction or avoidance in kidney impairment
•
Lack of flexibility in dosing
•
Short half-life mandates strict compliance
•
Limited availability of lab assays to measure anticoagulant effect
•
Lack of antidote
•
Higher drug acquisition costs
•
Fewer studied/approved indications (e.g., valves, ACS)
Bauer KA. ASH Education Book 2013; 1:464-470
Majeed A, et al. Circulation 2013; 128)21): 2325-32
•
•
Varies by:
–TSOAC
–Indication
–Country
May require adjustment for:
–Renal impairment
–Age
–Weight
–Drug interactions
–A combination of the above
Apixaban
Non-valvular
atrial
fibrillation
5 mg PO BID
2.5 mg PO BID*
VTE
prophylaxis
(orthopedic)
2.5 mg PO BID
VTE
treatment
and
prevention of
recurrence
N/A
Dabigatran
Rivaroxaban
150 mg PO BID
75 mg PO BID*
20 mg PO daily
15 mg PO daily*
CrCl <15 mL/min
Avoid use
CrCl <15 mL/min
Avoid use
N/A
10 mg PO daily
CrCl <30 mL/min
Avoid use
CrCl <30 mL/min
Avoid use
150 mg PO BID after 5-10 15 mg PO BID x 21 days,
days of parenteral
then 20 mg PO daily
anticoagulation
CrCl <30 mL/min
Avoid use
CrCl <30 mL/min
Avoid use
* Adjusted for renal impairment, drug interactions, age, low weight or a combination of these factors
 Treatment doses of rivaroxaban should be taken with largest meal of the day
•
No contraindication to TSOAC
– e.g., pregnancy, mechanical valve
•
Good compliance history or highly likely to be compliant with
medication and follow-up plan
•
Adequate organ function
•
Lack of significant drug-drug interactions with TSOACs
(e.g. azoles, macrolides, antiepileptics, protease inhibitors,
antacids, several cardiac medications)
•
Confirmed ability to obtain medication longitudinally
Ageno W, et al. J Thromb Haemost 2013; 11: 177-9.
Appropriate patient selection
Laboratory measurement
Peri-procedural management
Switching between agents
Management of severe bleeding
A 46-year-old male on rivaroxaban x 2 weeks for acute PE presents to
the ED with severe GI bleed. Labs and vitals: SCr 2.3 mg/dL,
Hgb/Hct 4.2/12, BP 90/50, HR 120s.
Which of the following labs would be most helpful in assessing for
presence of rivaroxaban?
A. Ecarin clotting time (ECT)
B. Prothrombin time (PT)
C. Activated partial thromboplastin time (aPTT)
D. Thrombin time (TT)

Increased specificity for target inhibition

Predictable pharmacokinetic and pharmacodynamic response

Minimal dietary effect

Less intrasubject and intersubject variability

Wide therapeutic index

Do not require routine monitoring
◦ Dose is not adjusted based on laboratory measurements
◦ No “therapeutic ranges” are provided
•
When might measurement of a TSOAC be indicated?
– Determine presence and quantity of drug
• Urgent or emergent invasive procedure
• Neuraxial anesthesia
• Major trauma
• Potential thrombolysis in acute thrombosis
• Assessing compliance
• Hemorrhagic or thrombotic complications
– Assess drug accumulation
• Diminished/changing renal function
• Hepatic impairment
• Accidental or intended overdose
• Drug interactions
Adcock DM. ASH Education Book 2012 ; 2012 (1): 460-65.
Garcia D et al. J Thromb Haemost 2013; 11: 245-52.
Tripodi A. Blood 2013; 121: 4032-35.
•
Routine coagulation assays
– Activated partial thromboplastin time (aPTT)
– Prothrombin time (PT)
– Helpful in determining relative drug concentration (qualitative)
– Readily available in most reference labs
•
Specialty coagulation assays
– Thrombin time (TT)
– Dilute thrombin time (dTT)
– Ecarin clotting time (ECT)
– Chromogenic Anti-Xa
– Determine measured drug concentration (quantitative)
– Not readily available nor standardized
– Research or investigational use only at this point
Measurement of TSOACs
Test
Dabigatran
aPTT*
↑↑
Rivaroxaban
Apixaban
↑
↑/ no effect
↑/ no effect
PT*
↑
↑↑
TT
↑↑↑
No effect
No effect
ECT
↑↑
No effect
No effect
No effect
↑↑
↑↑
Anti-Xa**
*Variability by reagent/instrumentation
**Drug-specific
TT = thrombin time
ECT = ecarin clotting time
Hillarp AJ, Thromb Haemost 2011;9:133-9.
Funk DM, Hematology 2012:460-465.
Frost et al, Br J Clin Pharmacol 2012;75:476.
Garcia D, et al. J Thromb Haemost 2013; 11: 245-52.
“Rules of Thumb”
Dabigatran
With 150 mg twice daily dosing, peak aPTT ~2x control
Elevated aPTT = drug present
Normal aPTT = minimal drug effect
Normal thrombin time (TT) = absence of drug effect
PT should not be used (relatively insensitive to dabigatran)
Rivaroxaban
With rivaroxaban 20 mg daily, peak PT ~1.5x control
Elevated PT = drug present
Elevated anti-Xa (drug-specific) = drug present
Normal PT = minimal drug effect
aPTT should not be used (some reagents relatively insensitive)
Appropriate patient selection
Laboratory measurement
Peri-procedural management
Switching between agents
Management of severe bleeding
A 62-year-old male with atrial fibrillation (CHADS2 score of 2 for DM, HTN)
on a TSOAC for stroke prevention is scheduled to undergo total knee
replacement in a few weeks.
Labs: SCr 0.7 mg/dL, weight 83 kg, Hgb 10.2, Hct 31
Which of the following describes the best course of action for his periprocedural anticoagulation?
A. Do not interrupt TSOAC therapy for this procedure
B. Hold TSOAC for 2-3 half-lives prior to this low bleed risk procedure
C. Hold TSOAC for 4-5 half-lives prior to this high bleed risk procedure
D. Hold TSOAC for 5 days prior to procedure and use LMWH as bridging
therapy

~250,000 patients annually in the US evaluated for
anticoagulation management around elective procedures

Rapid onset/offset of TSOACs precludes need for peri-operative
bridging with heparin or LMWH

Key question: Does anticoagulation need to be interrupted?

Timing of cessation and resumption of TSOAC is based on:
◦ Patient’s renal function
◦ Half-life of TSOAC
◦ Type of procedure and anesthesia
Spyropolous AC, et al. Blood 2012; 120(15): 2954-62.
Spyropolous AC, et al. Blood 2012; 120(15): 2954-62
Baron TH, et al. N Engl J Med 2013; 368: 2113-24.
• Management of Anticoagulation in the Peri-procedural Period (MAP) Tool
• Available at http://qio.ipro.org/drug-safety/drug-safety-resources or
http://excellence.acforum.org/
Risk
Assessment
High Bleed Risk Low Bleed Risk
High
thromboembolic
risk
Moderate
thromboembolic
risk
Low
thromboembolic
risk
Interrupt
TSOAC
Consider
interrupting
TSOAC
Interrupt
TSOAC
Minimal Bleed
Risk
Do not interrupt
TSOAC

Cessation of TSOAC
◦ Dependent on patient’s renal function and half-life of
TSOAC
 Half-life ranges from 6-17 hours, depending on TSOAC
 Will be prolonged with renal impairment
 May almost double in severe impairment
 May require longer pre-op hold time
◦ Dependent on type of procedure
 Low bleed risk: hold for 2-3 half-lives

High bleed risk: hold for 4-5 half lives
Stangier J, et al. Clin Pharmacokinet 2010; 49(4): 259-68.
Spyropolous AC, et al. Blood 2012; 120(15): 2954-62.

Resumption of TSOAC
◦ TSOACs have rapid onset of anticoagulant effect (~1-4 hours)
 Analogous to using LMWH
 Caution with resuming too soon or too aggressively
◦ Timing of resumption dependent on type of procedure
 Low bleed risk: resume 24 hours post-op
 High bleed risk: resume 48-72 hours post-op
◦ May consider “step-up” approach
 Lower or prophylactic dose of TSOAC for initial 24-48 hours
 If tolerated, increase to treatment dose TSOAC at 48-72
hours
Spyropolous AC, et al. Blood 2012; 120(15): 2954-62.
•
May need to confirm absence of anticoagulant effect
– Emergent procedures
– Planned use of spinal or epidural anesthesia
– Ensure use of appropriate lab parameter
•
Delayed resumption of TSOAC
– Patient unable to take PO post-procedure
– Concern for impaired gastrointestinal absorption (e.g., post-op
ileus)
– Epidural or spinal anesthesia
– Consider use of parenteral anticoagulant until patient can be
appropriately switched to TSOAC
Spyropolous AC, et al. Blood 2012; 120(15): 2954-62.
Appropriate patient selection
Laboratory measurement
Peri-procedural management
Switching between agents
Management of severe bleeding
A 71-year-old female on dabigatran for NVAF (CHA2DS2VASc = 6) and
recurrent VTE was admitted for ACS and emergently taken to the cath lab
for percutaneous coronary intervention (PCI). She was found to have multivessel disease and had 2 drug-eluting stents placed, which will require dual
antiplatelet therapy.
Which of the following antithrombotic strategies would be the best option
for her?
A. Resume dabigatran along with dual antiplatelet therapy
indefinitely
B. Stop dabigatran. Overlap LMWH and warfarin until INR
>2, along with antiplatelet therapy
D. Stop anticoagulation and continue only dual antiplatelet
therapy
•
•
•
Reason for switching from parenteral to oral anticoagulant
– Facilitate longer-term outpatient management
Reasons for switching from warfarin to TSOAC
– Drug intolerance
– Therapeutic failure
– Patient preference
Reasons for switching from TSOAC to warfarin
– Drug intolerance
– Therapeutic failure
– Patient preference
– New comorbidity or contraindication
• Worsening renal function
• Mechanical heart valve
• Acute coronary syndrome (ACS) requiring dual antiplatelet therapy
Abo-Salem E, et al. J Thromb Thrombolysis 2014; 37: 372-79.

Can place patients at undue risk for adverse events
◦ e.g., bleeding or thrombosis

Requires a “carefully constructed and thoughtful approach”

Should be based on:
◦ Pharmacokinetic profile of each anticoagulant
◦ Appropriate laboratory assessment of patient’s coagulation
status
◦ Patient’s renal function
Abo-Salem E, et al. J Thromb Thrombolysis 2014; 37: 372-79.
•
Unfractionated heparin
– Short half-life precludes need for lag time until alternative
anticoagulant is initiated
•
TSOACs and SQ injectables (LMWH, fondaparinux)
– Longer half-life requires lag time until alternative
anticoagulant is initiated
– Start alternative anticoagulant when the next dose of original
anticoagulant would be due
•
Warfarin
– Extremely long half-life requires confirmed offset via INR
– Slow onset may require overlap of rapid-acting anticoagulant
Appropriate patient selection
Laboratory measurement
Peri-procedural management
Switching between agents
Management of severe bleeding
A 62-year-old female on apixaban 2.5 mg PO BID for VTE prophylaxis
after a total hip arthroplasty presents to the ED with mild hematuria.
She is hemodynamically stable. When asked, she states she last took
her apixaban yesterday morning, and missed her evening dose due to
not feeling well.
What are options for managing her bleeding episode?
A. Hemodialysis to remove the apixaban
B. Oral activated charcoal to remove the apixaban
C. Concentrated factors (PCC, aPCC, rFVIIa) to reverse apixaban
D. Supportive care and investigate for source of the bleed
•
General approaches
– Hold anticoagulation
– Determine time of last ingestion
– Tincture of time (short half-lives)
– Fluid resuscitation to promote renal excretion
– Transfusion of blood products
– Attempt to identify and address source of bleed
– Mechanical compression
– Have specialty services on standby
•
If inadequate response, consider reversal strategies
Seigal DM, Cuker A. Drug Discov Today 2014. [Epub ahead of print] PMID: 24880102.
•
Clinical outcome data on the efficacy of PCC, aPCC and rFVIIa for the
reversal of TSOACs are lacking
•
Available evidence is limited (healthy human volunteers, animal models,
in vitro studies) with conflicting results
•
These agents may be considered in addition to maximum supportive
measures in patients with severe/life-threatening bleeding
•
The net clinical benefit should be considered in light of their
prothrombotic potential (~ 1.4% for PCC; up to 10% with rFVIIa)
•
Specific reversal agents are in development
Dentali F. Thromb Haemost. 2011 Sep;106(3):429-38. PMID: 21800002.
Levi M. N Engl J Med. 2010 Nov 4;363(19):1791-800. PMID: 21047223.
Seigal DM, Cuker A. Drug Discov Today 2014. [Epub ahead of print] PMID: 24880102.
Kaatz S. Am J Hematol. 2012 May;87 Suppl 1:S141-5. PMID: 22473649.
•
TSOACs may provide a viable alternative to traditional
anticoagulants in appropriately selected patients
•
Optimal use of TSOACs requires familiarity with:
–Pharmacokinetic/ pharmacodynamic profiles
–Various dosing strategies
–Laboratory measurement
–Peri-procedural strategies
–Switching strategies
–General approaches to bleed management
–Familiarity with reversal strategies
Thank you