4/7/2014 Lab Results Financial disclosure Follow Up Lab Tests

4/7/2014
Lab Results
• PT: 18.5 seconds
(12.0 – 14.5)
• PTT: 80.2 seconds
(24 – 39)
• Platelet count: 265 K/uL (160 – 400 K)
New Anticoagulants
Are we going in a new direction?
Karen Levisen MT(ASCP)SH
Financial disclosure
Follow Up Lab Tests
• Karen Levisen is employed by Diagnostica
Stago, Inc.
• Mixing study
- No correction with addition of NPP
• Factor VIII Activity
- Shows a non-parallel increase of activity as
the dilution increases
o 1:20 = 25%
o 1:40 = 50%
o 1:80 = 80%
Scenario
What Is The Answer?
• 87 yr old female presents to Hematologist for
evaluation of new bruising
• Lab work ordered includes PT, PTT and platelet
count
•
•
•
•
Inhibitor?
Factor deficiency?
Platelet dysfunction?
What additional information do we need?
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Question: What is the drug history?
New Anticoagulants
• Patient is taking Pradaxa (Dabigatran)
• Dabigatran etexilate
- Oral medication, absorbed in GI, becomes the
active form dabigatran.
-
Bioavailability is 6.5%
Maximum concentrations achieved in 1.5 – 3 hrs
Half life is 14 – 17 hrs
About 80% excreted in the active form by the kidneys
Drug interaction minimal
Food interaction not significant
Traditional Anticoagulant Therapy
New Anticoagulants
• LMWH is widely used in both outpatient and
inpatient settings for DVT and PE
• When UFH is used, it is started at or near the same
time as Coumadin
- Achieves a therapeutic INR as quickly as possible
- Heparin is maintained until a therapeutic INR
is reached and stabilized
New Anticoagulants
• Rivaroxaban (Xarelto)
-
Oral Anti-Xa inhibitor
Inhibits free and clot-bound Anti-Xa by 20 – 61%
Peak levels 1 – 4 hrs post administration
Half life about 12 hrs
Metabolized in liver, kidneys and some excreted as
active drug
New Anticoagulants
• Dabigatran (Pradaxa®) Indications1:
- Reduce the risk of stroke and systemic embolism in patients with
non-valvular atrial fibrillation
• Rivaroxaban (Xarelto®) Indications2:
- Reduce the risk of stroke and systemic embolism in patients with
non-valvular atrial fibrillation
- Treatment of DVT/PE
- Reduction in the risk of recurrence of DVT/PE
- Prophylaxis of DVT following hip or knee replacement surgery
• Apixaban (Eliquis®) Indications3:
- Reduce the risk of stroke and systemic embolism in patients with
non-valvular atrial fibrillation
- Prophylaxis of DVT following hip or knee replacement surgery
• Apixaban (Eliquis)
- Selective inhibitor of FXa
- Decreases thrombin generation and prevents clot
formation
- Bioavailability is approximately 50%, maximum
concentration 3-4 hours after ingestion
- Half life is approximately 12 hours
- No known antidote
• More in the queue (Betrixaban)
1
2
3
Pradaxa® Package Insert (12/2012), Boehringer-Ingelheim
Xarelto® Package Insert (3/2013), Janssen Pharmaceuticals
Eliquis® Package Insert (12/2012), Bristol-Myers Squibb
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Current Trends In Anticoagulation
What Is The Excitement?
• Oral doses
- Outpatient status
- Easy to administer
• Per manufacturers, no need to monitor
- Follow-up is minimal
- Patients are happier
What Is The Difference?
Safety and Efficacy Studies
Enoxaparin
Dabigatran
Etexilate 150 mg
Dabigatran
Etexilate 220 mg
DVT, PE, and all-cause mortality (%)
• New anticoagulants have different targets
- Dabigatran
o Direct thrombin inhibitor
- Rivaroxaban and Apixaban
o Direct Factor Xa inhibitor
P
P
RE-NOVATE (THR)
6.7
8.6
<.0001*
6.0
<.0001*
RE-MOBILIZE (TKR)
25.3
33.7
.0009†
31.1
.02†
RE-MODEL (TKR)
37.7
40.5
.003*
36.4
.017*
Major Bleeding (%)
RE-NOVATE (THR)
1.6
1.3
2.0
RE-MOBILIZE (TKR)
1.4
0.6
0.6
RE-MODEL (TKR)
1.3
1.3
1.5
THR = total hip replacement; TKR = total knee replacement
*Noninferior to enoxaparin.
†Inferior to enoxaparin.
Sites of Action
Safety and Efficacy studies
Application
AF Major/CRNM
HR/TKR
Major/CRNM
Warfarin
Enoxaprin
3.09/3.00
Apixaban
0.82/5.0
0.68/4.8
2.13/2.08
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How Do These Drugs Affect Testing?
References for Studies:
•Eriksson BI, Dahl OE, Rosencher N, , et al. Dabigatran etexilate versus
enoxaparin for prevention of venous thromboembolism after total hip
replacement: A randomised, double-blind, non-inferiority trial. Lancet.
2007;370:949-956.
•The RE-MOBILIZE Writing Committee. The oral thrombin inhibitor dabigatran
etexilate vs the North American enoxaparin regimen for the prevention of venous
thromboembolism after knee arthroplasty surgery. J Arthroplasty. 2009;24:1-9.
• Studies published in Europe
• Numerous analyzers and reagents
• Includes POC
•Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs.
subcutaneous enoxaparin for the prevention of venous thromboembolism after
total knee replacement: The Re-model randomized trial. J Thromb Haemost.
2007;5:2178-2185.
•Apixaban Medication Guide and Package Insert, March 2014.
What is the problem?
Dabigatran’s effects:
• No established FDA-approved test to directly
measure any of these drug levels
• PT: Elevated values, varying sensitivities
depending upon which reagents were used
- No assay to monitor these drugs
• No specific reversal agents
• Levels can become dangerous in certain
populations
- Kidney function important (GFI< 30 = contraindicated)
• PTT: Elevated values with a steep increase at
low values of drug and leveling off
• FIB: Could falsely underestimate levels in
certain reagent/analyzer platforms
• ATIII: Falsely high results with clotting assays, but
chromogenic assays essentially not affected
• APCR: Normalizing of ratio, potentially causing
some heterozygotes to be seen as normal
Lindahl, T.L., et.al. Thrombosis and Haemostasis, 105.2, 2011.
The Ideal Anticoagulant
Rivaroxaban and Apixaban effects:
Source: Schulman, Majeed; Sem Thromb/Hemost 2012; 38
Characteristic
Advantage
Dabigatran
VKA
LMWH
Oral
Easy to take
++
++
-
Predictable
Fixed dose
+
-
+
Rapid onset
No need for
bridging
+
-
+
Little interaction
Easy to use
+
-
+
Few adverse
events
Safety
+
-
+
Combined elimination
route
Useful in renal
impairment
-
+
-
Availability of effective
antidote
Easy to manage
bleeding
-
++
+
• PT: dose dependent increase in seconds
- INR conversion did not reduce the variability
of results with different reagents and platforms
• aPTT: less affected compared to PT
• TEG: wide variability
• dRVV, HepTest and PICT show non-linear
increases in clotting times
– Samana, M.M. et al, Thrombo Haemost, 2010.
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Measurement of Dabigatran
vanRyn, et al; Thromb and Haemost; 2010;103; 1116-1127
• PT and PTT limited to a qualitative type of
analysis
• ECT specifically designed to measure DTI’s but
no calibrators approved for Dabigatran
• Dilute TT shows a linear response curve over
therapeutic range, but not specific to Dabigatran
Why is This Good News?
• Per 2013 ISTH recommendations, there are clinical
circumstances in specific patients when measurement of the
anticoagulant effect will be required such as:
- Bleeding
- Before surgery or invasive procedure when patient has taken drug in
previous 24 hours, or longer if creatinine clearance (CrCl) is < 50ml/min
- Identification of sub- or supra-therapeutic levels in patients taking other
drugs that are known to significantly affect pharmacokinetics
- Identification of sub- or supra-therapeutic levels in patients at extremes
of body weight
- Patients with deteriorating renal function
- Peri-operative management
- Reversal of anticoagulation
- Suspicion of overdose
- Assessment of compliance in patients suffering thrombotic events while
on treatment (although this application may be limited by the short half
life)
Baglin, T. 2013 Measuring Oral Direct Inhibitors (ODIs) of thrombin and factor Xa: A
recommendation from the Subcommittee on Control of Anticoagulation of the Scientific and
Standardisation Committee of the International Society on Thrombosis and Haemostasis.
International Society on Thrombosis and Haemostasis (Accepted Article). doi:
10.1111/jth.12149
What are the consequences?
“If a patient on dabigatran has a prolonged
APTT over 90 seconds and a PT/INR greater
than 2.0, overdosing or accumulation of
dabigatran should be considered.”
Lindahl, T. L. et. al.
Anti-Xa assay for Rivaroxaban and
Apixaban
• Chromogenic test based upon a competition
principle
- Hydrolysis of the substrate by Anti-Xa
- Inhibition of the Factor-Xa by Rivaroxaban
or Apixaban
• Results in ng/ml from a standard curve
established using specific standards
What is the Good News?
More good news:
• Direct factor Xa inhibitors appear to be favored
in the most recent studies 1
• Phase 2 study of a recombinant protein
(PRT4445) developed by Portola
Pharmaceuticals, Inc. which will potentially
reverse the two anti-Xa inhibitors
• FDA recognized the lack of an effective reversal
agent as a significant unmet clinical need when
the two drugs were approved
• Mechanism of action based upon the similar
molecular structure of the drug to Factor Xa
- Dabigatran getting mixed reviews 1
- Emphasis on targeting farther up in cascade
• Anti-Xa assays are already cleared for heparin
monitoring
- Specific calibrators and controls are available for
Rivaroxaban and Apixaban (Currently RUO status)
- Development for additional direct factor Xa inhibitors
is underway
o 1 The heart.org/heartwire 3/18/2013
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What is the Role of The Lab?
• Offer meaningful tests to reflect the clinical
status of our patients
• Consult with clinicians when questions appear
concerning these new drugs
• Stay up to date by reading journals, subscribing
to medical education services
• Ask your hemostasis vendor for assistance
Questions?
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