practical issues of anticoagulant acceptance ......comparison of the effi cacy and safety of new...
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PRACTICAL ISSUES OF ANTICOAGULANT ACCEPTANCE IN
AVIATION MEDICINE
S. BISCONTE(1), A. HORNEZ(2), J. MONIN(2), D. DUBOURDIEU(2), X. ZIRPHILE(3), S. NGUYEN(1), O. MANEN(2),E. PERRIER(2).
87th ASMA ANNUAL SCIENTIFIC MEETING
ATLANTIC CITY - April 24 - 28, 2016
(1) Aeromedical Center, Robert Picqué Military Hospital, Bordeaux, France (2) Aeromedical Center, Percy Military Hospital, Clamart, France
(3) Cardiology, Robert Picqué Military Hospital, Bordeaux, France
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Disclosure Information 87th AsMA Annual Scientific Meeting
Sebastien BISCONTE
I have no financial relationships to disclose.
I will not discuss off-label use or
investigational use in my presentation.
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For 60 years, vitamin K antagonists (e.g., warfarin sodium) were the only available oral anticoagulant medications
Benefit / Risk Balance ! incapacitation !Thromboembolism .. stroke ! Intra cranial bleeding… ! consequences on flight safety
Evolution of knowledge ! Fit to fly with limitations
! Raises new problems for the flight surgeon
The advent of Direct Oral Anticoagulants (DOACs)
First use in France : 2008
! Raises some problems for the flight surgeon
We will only discuss about oral medication: VKA & DOACs heparin, specific anticoagulants (danaparoïde…)
Only prophylaxic treatment
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Why were VKA initially prohibited for pilots ?
It’s a family problem:
" an unpredictable dose-response relationship
" multiple drug interactions
" multiple diet interactions
! Narrow therapeutic index
Variable dietary control during flight can cause problems.
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Why were VKA initially prohibited for pilots ?
It’s a family problem:
! Narrow therapeutic index
" <65% of time in the therapeutic zone
" 0.25% fatal bleeding
" 1% major bleeding
" 6.5% minor bleeding
# 15% of patients having at least one minor event a year
Initially Prohibited for pilots in France
Stroke Intracranial Bleeding
Flight safety
Palareti Lancet 1996
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Medical regulation changes
Why ? - Limited bleeding risk in the
therapeutic zone
- Knowledge on anticoagulants in specific population
« young » population No comorbidity High intellectual ability
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Medical regulation changes
Why ? - Limited bleeding risk in the
therapeutic zone
- Knowledge on anticoagulants in specific population
- Identification of bleeding risk factor
Major bleeding risk : - intracranial hemorrhage,
- bleeding requiring hospitalization, - Hb drop of more than 2g/dL for systemic anticoagulation in pts with atrial fibrillation
Camm AJ. Eur Heart J. 2010 Pisters R. Chest. 2010 .Lip GYHEuropace. 2011
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Medical regulation changes
Why ? - Knowledge on anticoagulants
and take into account work accidentology due to VKA
- Limited risk in the therapeutic zone
- Identification of bleeding risk factor (limited in air crew members)
- French to European regulation
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European regulation for civil aircrew Implementing Rules:
« Applicants with an established history or diagnosis of cardiovascular condition requiring systemic anticoagulant therapy
shall be referred to the licencing authority »
Acceptable means of compliance
Referred to the licencing authority Multi-pilot limitation
- What is really a stable anticoagulation ? « 6-5-4 rule »
What about DOACs?
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Case report
Pilote – 50 yo Class 3 50 flight hours - Aortic dissection - Stanford type A - Biscupid aortic valve
! Bentall procedure Treatment: Bisoprolol 5mg
Fluindione 20mg
Is VKA the only problem ?
First step: evaluation of underlying disease
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Case report
Pilote – 50 yo Class 3 50 flight hours - Aortic dissection - Stanford type A - Biscupid aortic valve
! Bentall procedure No surgery complication Asymptomatic Good fonction of the mechanical
valve No arrythmias Treatment: Bisoprolol 5mg
Fluindione 20mg
First step: evaluation of underlying disease
Is VKA the only problem ?
o Symptoms o Complications o Prognosis o Consequences on flight safety
o … and treatment
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Case report
Pilote – 50 yo Class 3 50 flight hours - Aortic dissection - Stanford type A - Biscupid aortic valve
! Bentall procedure No surgery complication Asymptomatic Good fonction of the mechanical
valve No arrythmias Treatment: Bisoprolol 5mg
Fluindione 20mg
Stable anticoagulation ? ! 6-5-4 Rule ! INR target range : 2-3
month
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Case report
Pilote – 50 yo Class 3 50 flight hours - Aortic dissection - Stanford type A - Biscupid aortic valve
! Bentall procédure No surgery complication Asymptomatic Good fonction of the mechanical
valve No arrythmias Treatment: Bisoprolol 5mg
Fluindione 20mg
Stable anticoagulation ? ! 6-5-4 Rule ! INR target range : 2-3
month
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Case report
Pilote – 50 yo Class 3 50 flight hours - Aortic dissection - Stanford type A - Biscupid aortic valve
! Bentall procédure No surgery complication Asymptomatic Good fonction of the mechanical
valve No arrythmias Treatment: Bisoprolol 5mg
Fluindione 20mg
Stable anticoagulation ? ! 6-5-4 Rule ! INR target range : 2-3
month
6-5-4 rule is a theoretical rule Anticoagulant stability is a case by
case medical evaluation
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Case by case evaluation
the significance of abnormal INR depends on the medical condition
Bleeding
Thromboembolism Thromboembolism CHA2DS2 VASC
HASBLED
Bleeding
If phlebitis
If aortic valve
Prophylaxis only
Bleeding
Thromboembolism
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- Dabigatran
- Apixaban
- Rivaroxaban
- Edoxaban
• Prophylaxisinorthopaedics
• Prophylaxisinnon-valvularAfib• TreatmentandprophylaxisofrecurrenceinTEdisease
• NotformechanicalvalveApprovedEMA/FDA;notinFrance
UpdatedEuropeanHeartRhythmAssocia?onPrac?calGuideontheuseofnon-vitaminKantagonistan?coagulantsinpa?entswithnon-valvularatrialfibrilla?on.HeinHeidbuchel,PeterVerhamme,MarcoAlings,MaDhiasAntz,Hans-ChristophDiener,WernerHacke,JonasOldgren,PeterSinnaeve,A.JohnCamm,andPaulusKirchhof.Europacedoi:10.1093/europace/euv309
Different DOACs
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Efficacy: DOACs vs VKA
At least as effective as VKA
Dataregardingfulldosage.
Chris?anTRuff,RobertPGiugliano,EugeneBraunwald,ElaineBHoffman,NaveenDeenadayalu,MichaelDEzekowitz,AJohnCamm,JeffreyIWeitz,BasilSLewis,AlexanderParkhomenko,TakeshiYamashita,EllioTMAntman.ComparisonoftheefficacyandsafetyofneworalanQcoagulantswithwarfarininpaQentswithatrialfibrillaQon:ameta-analysisofrandomisedtrials.Lancet2014;383:955–62.
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Safety: DOACs vs VKA
Less major bleeding. Less Intracranial bleeding.
More GI bleeding.
Chris?anTRuff,RobertPGiugliano,EugeneBraunwald,ElaineBHoffman,NaveenDeenadayalu,MichaelDEzekowitz,AJohnCamm,JeffreyIWeitz,BasilSLewis,AlexanderParkhomenko,TakeshiYamashita,EllioTMAntman.ComparisonoftheefficacyandsafetyofneworalanQcoagulantswithwarfarininpaQentswithatrialfibrillaQon:ameta-analysisofrandomisedtrials.Lancet2014;383:955–62.
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DOACs interactions
Some drug interactions But no diet interaction
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Possiblemonitoring
Possiblesupervision
DOACs monitoring
Without proportionality
Expensive…
Elimina?onhalf-life
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DOACs vs DOACs
• NoDOACsVsDOACsstudy.• Atfulldosage:
ApixabanVsVKA:seemstobemoresaferDabigatranVsVKA:seemstobemoreefficient
• Nearhalf-life-->samestabilityConnolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med.
17 sept 2009;361(12):1139‑1151. (RE-LY). Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al. Dabigatran versus Warfarin in the Treatment of Acute Venous
Thromboembolism. N Engl J Med. 10 déc 2009;361(24):2342‑2352. (RECOVER). Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med. 8 sept
2011;365(10):883‑891. (ROCKET-AF). The Einstein Investigators, Rupert Bauersachs, Scott D. Berkowitz, Benjamin Brenner. Oral Rivaroxaban for Symptomatic Venous Thromboembolism. N
Engl J Med. 23 déc 2010;363(26):2499‑2510. (EINSTEIN). Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med.
15 sept 2011;365(11):981‑992. (ARISTOTLE). Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Oral Apixaban for the Treatment of Acute Venous Thromboembolism. N Engl J Med.
29 août 2013;369(9):799‑808. (AMPLIFY). Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med.
2013;369(22):2093–2104. (ENGAGE-AF). Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406–15.
(HOKUSAI).
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Place of DOACs in aviation medicine
Use DOACs doesn’t change: • evaluation of underlying
cardiopathy
• Requirement to refer to the licencing authority
• Requirement of Multi-pilot limitation
Main Advantages of DOACs : • At least as effective as VKA • Less intracranial bleeding • Less overall bleeding • No diet interaction • Less drug interactions
Main Disadvantages of DOACs: • Short half-time • Monitoring not easy
! New problematic compliance?
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DOACs compliance
Pharmocalogical test: - very expensive - without proportionnality
Short Half life ! stability of the last
few days Quality of relationship between
Aircrew members and fight surgeon +++
- Understand his disease - Importance of daily compliance
Aircrew members/flight surgeon relationship
If you have a reasonnable doubt and for first evaluation:
- Number and dates of prescriptions ! PT or aPTT
Delay ?
! 3 months
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The perfect anticoagulant still remains elusive; That’s why referring to licensing authority and multi pilot
license is always necessary .
However, the advent of the direct oral anticoagulants represents a real improvement.
DOACs are at least as safe and efficient as VKAs. The monitoring compliance difficulties
are not a real problem.
Like all new treatment in aviation medicine, anticoagulants require long term survey.
Take home message
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Thank you for your attention