IDELVION — the only rFIX therapy that delivers high steady-state factor levels with up to 14-day dosing *
2017 ; 31 ( 1 ): 77-84 .
You Made the Call
TRAINING and EDUCATION
You Make the Call
Each month in “ You Make the Call ,” we ’ ll pick a challenging clinical question submitted through the Consult-a-Colleague program and post the expert ’ s response . But , what would YOU do ? We ’ ll also pose a submitted question and ask you to send your responses . See how your answer matches up to the experts in the next print issue .
This month , Joel S . Bennett , MD , discusses the possibility of novel oral anticoagulant failure in a patient with deep vein thrombosis .
Clinical Dilemma :
I have a 53-year-old patient who works as a consultant with frequent travel in the United States . There is no significant past medical history , and the patient is very active . There is a family history of thrombophilia in the fifth decade . The patient presented with proximal deep vein thrombosis ( DVT ) and was discharged home on apixaban 10 mg twice daily . The patient presented to the emergency room 3 days later with sudden onset shortness of breath . The computed tomography angiography was positive for pulmonary embolism ( PE ). The patient is compliant with taking the prescribed dose of apixaban . The patient is currently on intravenous heparin . Is this failure of novel oral anticoagulant ( NOAC )? Is there any data to suggest switching to another NOAC ? What are the prescribing options ?
Experts Make the Call
Joel S . Bennett , MD Professor of Medicine Division of Hematology-Oncology Perelman School of Medicine University of Pennsylvania
The issue of anticoagulation failure is AMPLIFY trial who were initially treated for 7 days with often challenging . Whether a new thrombotic event is apixaban revealed a recurrence rate of 0.68 percent by day 7 , really new and , if so , whether the patient was adequately indicating that early recurrence is an uncommon event . 3 anticoagulated when the event occurred are often difficult Based on all of the above , I would put this patient back on to determine . This is even more difficult when a patient is apixiban , since it is at least as effective as warfarin ( with less treated with an NOAC , since dosing is not based on laboratory measurements that confirm the patient is actually However , if the patient is not achieving “ on-therapy range ”
bleeding ) and it is certainly more convenient than LMWH . adequately anticoagulated . apixaban blood levels ( i . e ., > 5th percentile trough levels ) despite taking the recommended apixaban doses , there are anti –
It is my opinion that the PE the patient suffered was not the result of anticoagulant failure for the following reasons : First , factor Xa activity assays specifically calibrated for apixaban anticoagulation is given after a venous thromboembolic event that could settle this concern . 4 , 5 ( VTE ) to prevent further thrombosis . It does not cause the lysis or organization of the existing thrombi . Thus , it would seem intuitively possible that for a period of time , a piece of an existing clot could “ break off ” and embolize until either endogenous clot lysis or organization occurs .
Second , reviews of the natural history of VTE have shown that asymptomatic clot extension is common during the initial phase of therapy when patients are treated with low-molecular-weight heparin ( LMWH ) or unfractionated heparin . 1 , 2 Further , the resolution of DVT in anticoagulated patients can be slow . Lastly , a sub-analysis of patients in the
Next Month ’ s Clinical Dilemma :
References 1 . Kearon C . Natural history of venous thromboembolism . Circulation . 2003 ; 107 ( 23 Suppl 1 ): I22-30 .
2 . Basu D , Gallus A , Hirsh J , Cade J . A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time . N Engl J Med . 1972 ; 287 ( 7 ): 324-27 .
3 . Raskob GE , Gallus AS , Sanders P , et al . Early time courses of recurrent thromboembolism and bleeding during apixaban or enoxaparin / warfarin therapy . A sub-analysis of the AMPLIFY trial . Thromb Haemost . 2016 ; 115 ( 4 ): 809-16 .
4 . Ward C , Conner G , Donnan G , Gallus A , McRae S . Practical management of patients on apixaban : a consensus guide . Thromb J . 2013 ; 11 ( 1 ): 27 .
5 . Samuelson BT , Cuker A . Measurement and reversal of the direct oral anticoagulants . Blood Rev .
DISCLAIMER : ASH does not recommend or endorse any specific tests , physicians , products , procedures , or opinions , and disclaims any representation , warranty , or guaranty as to the same . Reliance on any information provided in this article is solely at your own risk .
A pregnant 38-year-old female was strual complaints , had genitourinary noted to have factor XI ( FXI ) deficiency surgery for repair of reflux at 8 years when the assay was ordered because of of age with no bleeding . No one in her her Jewish heritage . family has bleeding problems or is
She has never had any heavy men- known to have FXI deficiency .
She is pregnant again , with FXI levels of 39-55 percent so far . Should I follow her with observation , reserving fresh frozen plasma for bleeding events ?
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34 ASH Clinical News April 2017
nosis of deep vein thrombosis ( DVT ). In this case , I would switch to therapeutic LMWH for one week , and then return to a DOAC thereafter , assuming that the patient is not on any medications that interact with a DOAC that would lower the effectiveness of apixaban , and that his body weight is less than 120 kg .
Dimitri Scarvelis , MD Ontario , Canada
First of all , there is no data to support changing to a NOAC . The underlying question is whether there is failure of the NOAC . The dyspnea may be related to pain . There was no mention of hypoxia , which would be more concerning . Heparin is not a good idea because it is difficult to get patients into the therapeutic range . LMWH would have been a better idea ; it is more reliable and a readily bioavailable drug . The only reason to use heparin would be if you thought this patient would benefit from thrombolysis and needed to stop the heparin . I would consider a month of lovenox , and would go back to a NOAC .
Lorinda A Coombs , PhDc , RN University of California San Francisco
San Francisco , CA
We asked , and you answered ! Here are a few responses from this month ’ s “ You Make the Call .”
For the full description of the clinical dilemma , and to see how the expert responded , turn to page 34 .
Clinical Dilemma :
A 53-year-old patient presented with proximal deep vein thrombosis and was discharged home on apixaban 10 mg twice daily . The patient presented to the emergency room three days later with sudden-onset shortness of breath . The computed tomography angiography was positive for pulmonary embolism . Is this failure of novel oral anticoagulant ( NOAC )? Is there any data to suggest switching to another NOAC ?
It is clearly a failure of apixaban . As in any other rare case of failure of anticoagulant therapy , provided the chosen drug was effectively administrated , my main concern is to diagnose the condition that leads to recurrence . Given the age of this patient , I would try to disclose an occult neoplasm and antiphospholipid syndrome . If the patient is stable , I would switch to enoxaparin 1 mg / kg three times a day until the workup is complete . Lupus anticoagulant can be a problem to study while on unfractionated heparin , but enzymelinked immunosorbent assays can be of value in this situation .
Jorge David Korin , MD Buenos Aires , Argentina
Is this failure of novel oral anticoagulant ( NOAC )? Yes . Is there any data to suggest switching to another NOAC ? No . What are the prescribing options ? Warfarin with international normalized ratio ( INR ) control or low-molecularweight heparin ( LMWH ).
Giuseppe Avvisati , MD , PhD Rome , Italy
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Important Safety Information
IDELVION is indicated in children and adults with hemophilia B ( congenital Factor IX deficiency ) for :
• On-demand control and prevention of bleeding episodes
• Perioperative management of bleeding
• Routine prophylaxis to prevent or reduce the frequency of bleeding episodes
IDELVION is not indicated for induction of immune tolerance in patients with hemophilia B .
IDELVION is contraindicated in patients who have had life-threatening hypersensitivity to the product or its components , including hamster proteins .
IDELVION is for intravenous use only .
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High and sustained Factor IX levels at steady state in clinical trials 1 ,†
IDELVION can be self-administered or administered by a caregiver with training and approval from a healthcare provider or hemophilia treatment center . Higher dose per kilogram body weight or more frequent dosing may be needed for pediatric patients .
Hypersensitivity reactions , including anaphylaxis , are possible . Advise patients who self-administer to immediately report symptoms of hypersensitivity , including angioedema , chest tightness , hypotension , generalized urticaria , wheezing , and dyspnea . If symptoms occur , discontinue IDELVION and administer appropriate treatment .
Development of neutralizing antibodies ( inhibitors ) to IDELVION may occur . If expected Factor IX activity plasma levels
Zero median annualized spontaneous bleeding rate ( AsBR ) when dosed at 7 or 14 days in clinical trials
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are not attained or bleeding is not controlled with appropriate dose , perform an assay to measure Factor IX inhibitor concentration . Factor IX activity assay results may vary with the type of activated partial thromboplastin time reagent used .
Thromboembolism ( eg , pulmonary embolism , venous thrombosis , and arterial thrombosis ) can occur when using Factor IX-containing products . In addition , nephrotic syndrome has been reported following immune tolerance induction in hemophilia B patients with Factor IX inhibitors and allergic reactions to Factor IX .
The most common adverse reaction ( incidence ≥1 %) reported in clinical trials was headache .
* In well-controlled patients 12 years and older , defined as 1 month without spontaneous bleeding on a weekly dose of ≤40 IU / kg .
†
Steady-state levels measured FIX at trough levels before each infusion every four weeks until week 92 at 7-day prophylaxis and week 104 at 14-day prophylaxis . FIX levels were 13 % when dosed every 14 days .
Reference : 1 . Data on file . Available from CSL Behring as DOF IDL-002 .
Please see brief summary of full prescribing information on following page .
USE1
,†
ZERO
BLEEDS
MEDIAN ASBR
I would not classify this as a failure of direct oral anticoagulant ( DOAC ) as the pulmonary embolism ( PE ) occurred within only three days of diag-
ASHClinicalNews . org
IDELVION is manufactured by CSL Behring GmbH and distributed by CSL Behring LLC . IDELVION ® is a registered trademark of CSL Behring Recombinant Facility AG . Biotherapies for Life ® is a registered trademark of CSL Behring LLC .
© 2016 CSL Behring LLC 1020 First Avenue , PO Box 61501 , King of Prussia , PA 19406-0901 USA www . CSLBehring-us . com www . IDELVION . com IDL16-12-0160 12 / 2016
Coagulation Factor IX ( Recombinant ), Albumin Fusion Protein
®
You Made the Call
TRAINING
You Make
ION
and EDUCAT
nosis of deep vein thrombosis (DVT). In
this case, I would switch to therapeutic
LMWH for one week, and then return to
a DOAC thereafter, assuming that the
patient is not on any medications that
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the effectiveness of apixaban, and that
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References
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thromboembo
heparin treatment
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history of venous
of monitoring
1. Kearon C. Natural
study of the value
(VTE) to prevent of the existing thrombi. time, a piece of
4-27.
J. A prospective
tion
of
Med. 1972;287(7):32
A, Hirsh J, Cade
time. N Engl J
for a period
lism and bleeding
lysis or organiza
2. Basu D, Gallus
thromboplastin
until either
thromboembo
y possible that
the activated partial
courses of recurrent AMPLIFY trial. Thromb Haemost.
off” and embolize
seem intuitivel
the
et al. Early time
P,
of
“break
Sanders
A sub-analysis
Gallus AS,
clot could
occurs.
rfarin therapy.
3. Raskob GE,
an existing
or enoxaparin/wa
organization
have
apixaban: a
during apixaban
clot lysis or
of patients on
history of VTE
9-16.
endogenous
management
2016;115(4):80
of the natural
common during
A, McRae S. Practical
G, Donnan G, Gallus
Second, reviews matic clot extension is
. Blood Rev.
4. Ward C, Conner Thromb J. 2013;11(1):27.
treated with
anticoagulants
asympto
patients are
the direct oral
consensus guide.
shown that
nated
and reversal of
of therapy when
) or unfractio
BT, Cuker A. Measurement
the initial phase eight heparin (LMWH
lated
5. Samuelson
4.
in anticoagu
2017;31(1):77-8
low-molecular-w the resolution of DVT patients in the
any
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and disclaims
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heparin. Further, Lastly, a sub-analysis
procedures, solely at your own risk.
be slow.
, products,
is
patients can
in this article
tests, physicians
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ER: ASH does or guaranty as to the
DISCLAIM
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representation,
a:
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Next Month
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